METHODS FOR TREATING MULTIPLE MYELOMA

SEQUENCE LISTING

This application contains a computer readable Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “258199061501(JBI6802USNP1)_Sequence_Listing.xml”, was created on Apr. 18, 2024 and is 26,376 bytes in size.

FIELD OF THE INVENTION

Methods of treating multiple myeloma are disclosed.

BACKGROUND OF THE INVENTION

Multiple myeloma (MM) is a cancer of the plasma cells. Mechanistically, multiple myeloma is characterized by production of monoclonal proteins (M-proteins) comprised of pathological immunoglobulins or fragments of such, which have lost their function. The proliferation of multiple myeloma cells leads to subsequent displacement from the normal bone marrow niche, while overproduction of M-proteins causes characteristic osteolytic lesions, increased susceptibility to infections, hypercalcemia, renal insufficiency or failure, and neurological complications.

Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, physical condition of the patient, and existing comorbidities. Therapeutic options include proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody drug conjugate, histone deacetylase inhibitor, nuclear protein export inhibitor, chimeric antigen receptor (CAR) T cell therapy and stem cell transplantation.

Despite these therapeutic achievements, the disease recurs and is associated with additional risk factors (e.g., comorbidities or increasing age), thus warranting the need for novel therapeutic approaches, such as new dosage and treatment regimens. In particular in the elderly population, for which stem cell transplantation is often not a viable option, and in patients with refractory disease who exhausted several therapies, multiple myeloma remains an incurable malignancy and an unmet medical need with significant morbidity and mortality. In particular, there remains a need for therapeutic regimens that achieve rapid, deep and durable clinical responses, while providing manageable safety profiles.

SUMMARY OF THE INVENTION

An embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody on a bi-weekly (Q2W) dosing schedule.

Another embodiment of the present invention provides a method of treating multiple myeloma in a subject in need thereof, the method comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody on a Q4W dosing schedule.

In certain embodiments, a method of treating multiple myeloma in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teclistamab) on a bi-weekly dosing schedule (Q2W) and/or a monthly dosing schedule (Q4W), wherein the subject has been diagnosed with multiple myeloma.

In certain embodiments, a method of treating multiple myeloma in a subject in need thereof comprises administering to the subject treatment doses of a BCMAxCD3 bispecific antibody on a bi-weekly dosing schedule (Q2W).

In certain embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.

In certain embodiments, the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

In certain embodiments, the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).

In certain embodiments, the Fc region of the BCMA-binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

In certain embodiments, the Fc region of the CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).

In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.

In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.

In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.

In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

In certain embodiments, the subject has relapsed or refractory multiple myeloma myeloma (e.g., the subject has had been treated with from 2 to 14 prior lines of therapy).

In certain embodiments, the subject has received at least three prior lines of therapy.

In certain embodiments, the subject has received at least four prior lines of therapy.

In certain embodiments, the subject has received at least five prior lines of therapy (penta-drug exposed).

In certain embodiments, the subject has received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

In certain embodiments, the subject has received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering to the subject one or more step-up doses of the BCMAxCD3 bispecific antibody prior to administering the first treatment dose of the BCMAxCD3 bispecific antibody.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of from about 1500 μg/kg to about 3000 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of about 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of about 3000 μg/kg.

In certain embodiments, the method comprises subcutaneously administering to the subject at least one treatment dose of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) and subsequently administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least one 28-day cycle of treatment, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least two 28-day cycles of treatment, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least three 28-day cycles of treatment, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least four 28-day cycles of treatment, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least five 28-day cycles of treatment, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least six 28-day cycles of treatment, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) for at least six months, and subsequently administering treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) until the subject achieves a partial response, a very good partial response, a complete response or a stringent complete response, as determined by IMWG response criteria, and subsequently administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) until the subject achieves a complete response or a stringent complete response, as determined by IMWG response criteria, and subsequently administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) until the subject achieves a partial response, a very good partial response, a complete response or a stringent complete response after four or more cycles of treatment, as determined by IMWG response criteria, and subsequently administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) until the subject achieves a partial response, a very good partial response, a complete response or a stringent complete response for six or more months, as determined by IMWG response criteria, and subsequently administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) until the subject achieves a complete response or a stringent complete response for six or more months, as determined by IMWG response criteria, and subsequently administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W).

In certain embodiments, each treatment dose amount of the BCMAxCD3 bispecific antibody administered on the weekly dosing schedule (QW) is the same treatment dose amount of the BCMAxCD3 bispecific antibody administered on the bi-weekly dosing schedule (Q2W).

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the weekly dosing schedule (QW) at a treatment dose of from about 1500 μg/kg to about 3000 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the weekly dosing schedule (QW) at a treatment dose of about 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the weekly dosing schedule (QW) at a treatment dose of about 3000 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the weekly dosing schedule (QW) at a treatment dose of about 1500 μg/kg, and then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of about 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W), and then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W).

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW), and then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W), and then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W).

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W), and if the subject achieves a partial response, a very good partial response, a complete response or a stringent complete response, then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W).

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W), and if the subject achieves a complete response or a stringent complete response, then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W).

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W), and if the subject achieves a complete response or a stringent complete response by cycle 12 of treatment or later, then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W).

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) for at least six months, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W).

In certain embodiments, the method comprises subcutaneously administering 1, 2 or 3 step-up doses of the BCMAxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose.

In certain embodiments, the method comprises subcutaneously administering step-up doses of 60 μg/kg and 300 μg/kg and 1500 μg/kg of the BCMAxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose.

In certain embodiments, the method comprises subcutaneously administering 1 or 2 step-up doses of the BCMAxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose.

In certain embodiments, the method comprises subcutaneously administering 2 step-up doses of the BCMAxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose.

In certain embodiments, the method comprises subcutaneously administering step-up doses of 60 μg/kg and 300 μg/kg of the BCMAxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose.

In certain embodiments, the method comprises subcutaneously administering step-up doses of the BCMAxCD3 bispecific antibody 2-4 days apart from each other, prior to subcutaneously administering the first treatment dose.

In certain embodiments, the method comprises subcutaneously administering one or more step-up doses of the BCMAxCD3 bispecific antibody prior to subcutaneously administering the first treatment dose, wherein the first treatment dose is administered 2-4 days after the last step-up dose.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg for a period of time, and then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg for six months or more, and then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg, and after the subject has a partial response, a very good partial response, a complete response or a stringent complete response for six months or more (according to IMWG criteria), then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg, and after the subject has a complete response or a stringent complete response for six months or more (according to IMWG criteria), then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg, and after the subject has a partial response, a very good partial response, a complete response or a stringent complete response after four 28-day treatment cycles or more (according to IMWG criteria), then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg for a period of time, then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg for a period of time, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg for a period of time, then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg for a period of time, and if the subject achieves at least CR (i.e., complete response or stringent complete response) by cycle 12 or later, then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering a first step-up dose of 60 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a second step-up dose of 300 μg/kg of the BCMAxCD3 bispecific antibody, then 2-4 days later subcutaneously administering a first treatment dose of 1500 μg/kg of the BCMAxCD3 bispecific antibody, then subcutaneously administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1500 μg/kg for a period of time, then subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of 1500 μg/kg for at least 6 months, and then subcutaneously administering the BCMAxCD3 bispecific antibody on a monthly dosing schedule (Q4W) at a treatment dose of 1500 μg/kg.

In certain embodiments, the subject achieves a clinical response that is a PR, or a VGPR, or a CR or a sCR.

In certain embodiments, the subject achieves a clinical response that is a CR or a sCR.

In certain embodiments, the clinical response is maintained for at least 6 months.

In certain embodiments, the clinical response is maintained for at least 1 year.

In certain embodiments, the clinical response is maintained for at least 18 months.

In certain embodiments, the clinical response is maintained for at least 2 years.

In certain embodiments, fewer infections occur in the subject (e.g., compared to a subject that remains on QW dosing).

In certain embodiments, fewer grade ≥3 infections occur in the subject (e.g., compared to a subject that remains on QW dosing).

In certain embodiments, the method achieves a decrease in new infections over time, in a population of subjects with RRMM (e.g., compared to subjects that remain on a QW dosing schedule).

In certain embodiments, the method achieves a decrease in new grade ≥3 infections over time, in a population of subjects with RRMM RRMM (e.g., compared to subjects that remain on QW dosing schedule).

Embodiments of the present invention also provide a method of treating multiple myeloma in a subject in need thereof, the method comprising prophylactically administering to the subject tocilizumab (toci) prior to administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody (e.g., teclistamab), wherein the method is effective in reducing the risk of cytokine release syndrome (CRS).

Embodiments of the present invention also provide methods for restarting therapy with a BCMAxCD3 bispecific antibody after a dose delay.

All methods described herein, however expressed, may be described as corresponding uses, in particular medical uses.

BRIEF DESCRIPTION OF THE FIGURES

The following figures form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these figures in combination with the description of specific embodiments presented herein.

FIG. 1 illustrates a summary of the MajesTEC-1 Clinical Study Design.

FIG. 2 illustrates a summary of the MajesTEC-1 dosing schedule.

FIG. 3 provides patient characteristics of the MajesTEC-1 Q2W cohort.

FIG. 4 provides infection rates from the MajesTEC-1 Q2W cohort.

DETAILED DESCRIPTION OF THE INVENTION

The disclosed methods can be understood more readily by reference to the following detailed description. It is to be understood that the disclosed methods are not limited to the specific methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods. All patents, published patent applications and publications cited herein are incorporated by reference as if set fourth fully herein.

As used herein, the singular forms “a,” “an,” and “the” include the plural.

Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

“About” when used in reference to numerical ranges, cutoffs, or specific values means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of an assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

“Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

“Antigen binding fragment” or “antigen binding domain” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments can be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab′)2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and/or the HCDR3 and the LCDR1, the LCDR2 and/or the LCDR3. VH and VL domains can be linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains can pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. WO1998/44001, WO1988/01649, WO1994/13804 and WO1992/01047.

“BCMA” refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA encompasses residues 1-54 of Q02223. Human BCMA comprises the amino acid sequence of SEQ ID NO: 1.

SEQ ID NO: 1

MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVK

GTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMA

NIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAME

EGATILVTTKTNDYCKSLPAALSATEIEKSISAR

“Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody can have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca cynomolgus (cynomolgus, cyno) or Pan troglodytes, or can bind an epitope that is shared between two or more distinct antigens.

“BCMAxCD3 bispecific antibody” refers to a bispecific antibody that specifically binds BCMA and CD3.

“Cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” can include a tumor.

“CD3” refers to a human antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta and CD3 gamma. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.

SEQ ID NO: 2

MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCP

QYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYP

RGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYY

WSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYS

GLNQRRI

SEQ ID NO: 3

DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDD

KNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENC

MEMD

“CH3 region” or “CH3 domain” refers to the CH3 region of an immunoglobulin. The CH3 region of human IgG1 antibody corresponds to amino acid residues 341-446. However, the CH3 region can also be any of the other antibody isotypes as described herein.

“Combination” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

“Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs can be defined using various delineations such as Kabat (Wu et al. J Exp Med 132: 211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196: 901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27: 55-77, 2003) and AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996). The correspondence between the various delineations and variable region numbering are described (see e.g. Lefranc et al. Dev Comp Immunol 27: 55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; Web resources, http://www_imgt_org). Available programs such as abYsis by UCL Business PLC can be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification. Preferably, the term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by the method of Kabat.

“Comprising” is intended to include examples encompassed by the terms “consisting essentially of” and “consisting of”; similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of” Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

“Fc gamma receptor” (FcγR) refers to well-known FcγRI, FcγRIIa, FcγRIIb or FcγRIII. Activating FcγR includes FcγRI, FcγRIIa and FcγRIII.

“Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. “Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, “human antibody” can contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. WO2009/085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.

“Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody can include substitutions in the frameworks so that the frameworks can not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

“Identity” refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent (%) sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

“Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and/or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated antibody” refers to an antibody that is substantially free of other cellular material and/or chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

“Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibody can be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

“Mutation” refers to an engineered or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration can be a substitution, insertion or deletion of one or more amino acids or polynucleotides.

“Negative minimal residual disease status” or “negative MRD status” or “MRD negative” refers to the PerMillionCount (i.e., a point estimate of malignant myeloma cells per million nucleated cells) in a patients on-study bone marrow sample relative to their reference bone marrow sample (i.e., Teclistamab treatment naïve bone marrow sample). Based on this PerMillionCount, each sample is determined to be positive or negative. Samples are positive if the PerMillionCount is greater than or equal to the limit of sensitivity, otherwise they are negative. Negative minimal residual disease status can be determined at a sensitivity of 0.01% (10⁻⁴), 0.001% (10⁻⁵) or 0.0001% (10⁻⁶). Negative minimal residual disease status was determined using next generation sequencing (NGS).

“Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.

“Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject.

“Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

“Refractory” refers to a cancer that is not amendable to surgical intervention and is initially unresponsive to therapy.

“Relapsed” refers to a cancer that responded to treatment but then returns.

“Step-up dose”—refers to a dose of an active agent that is administered to a subject prior to a treatment dose. A step-up dose is lower than the treatment dose. To prevent or lessen certain toxicities, such as cytokine release syndrome (CRS), a “priming” dose strategy may include one or more lower step-up dose(s) followed by higher treatment doses.

“Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Except when noted, the terms “patient” or “subject” are used interchangeably.

“T cell redirecting therapeutic” refers to a molecule containing two or more binding regions, wherein one of the binding regions specifically binds a cell surface antigen on a target cell or tissue and wherein a second binding region of the molecule specifically binds a T cell antigen. Examples of cell surface antigen include a tumor associated antigen, such as BCMA. Examples of T cell antigen include, e.g., CD3. This dual/multi-target binding ability recruits T cells to the target cell or tissue leading to the eradication of the target cell or tissue.

“Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

“Treat” or “treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

“Treatment dose”—refers to a dose of the active agent that is administered to a subject to treat a disease. A treatment dose may be administered at a regular dosing interval on a repetitive basis (e.g. weekly, biweekly, monthly). A treatment dose may be preceded by one or more step-up doses.

A patient that is “triple-class exposed” refers to a multiple myeloma patient that has previously been treated with (at a minimum) a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

“Tumor cell” or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new genetic material. Although transformation can arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation/cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo.

The numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise explicitly stated. Antibody constant chain numbering can be found for example at ImMunoGeneTics website, at IMGT Web resources at IMGT Scientific charts.

Conventional one and three-letter amino acid codes are used herein as shown in Table 1.

TABLE 1

Amino acid
Three-letter code
One-letter code

Alanine
Ala
A

Arginine
Arg
R

Asparagine
Asn
N

Aspartate
Asp
D

Cysteine
Cys
C

Glutamate
Gln
E

Glutamine
Glu
Q

Glycine
Gly
G

Histidine
His
H

Isoleucine
Ile
I

Leucine
Leu
L

Lysine
Lys
K

Methionine
Met
M

Phenylalanine
Phe
F

Proline
Pro
P

Serine
Ser
S

Threonine
Thr
T

Tryptophan
Trp
W

Tyrosine
Tyr
Y

Valine
Val
V

BCMAxCD3 Bispecific Antibodies and Uses Thereof

It is well-known in the art that drug development is an unpredictable field. The lack of predictability in the art is evidenced, for example, by health authority requirements (such as those of the Food and Drug Administration) to establish a safe and effective dosing regimen for each individual drug candidate in clinical trials. Over the last decade (2011-2020), only 7.9% of all developmental drug candidates achieved FDA approval from a Phase I clinical study. See Clinical Development Success Rates and Contributing Factors 2011-2020. The rate of success is even lower in oncology, such that only 5.3% of oncology drug candidates succeed.

In the field of oncology, even for a drug that already has an established dose in a particular indication, the Food and Drug Administration (FDA) recommends further clinical studies to identify an optimal dose for a new indication; otherwise, patients may be exposed to unreasonable and significant risk, among other potential deficiencies. See, e.g., Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases; Draft Guidance for Industry; January 2023).

In patients with relapsed or refractory disease who have exhausted several therapies, multiple myeloma remains an incurable malignancy and an unmet medical need with significant morbidity and mortality. The present inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that provide improved safety profiles over currently approved regimens while maintaining deep and durable efficacy.

Teclistamab (also known as TECVAYLI®) is the first BCMA-directed bispecific antibody approved for the treatment of patients with relapsed or refractory multiple myeloma. Teclistamab is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three or four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. The efficacy of teclistamab is continuing to be evaluated in patients with relapsed or refractory multiple myeloma in a multi-center clinical study (MajesTEC-1, NCT03145181 [Phase 1] and NCT04557098 [Phase 2]). The study has included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. In the MajesTEC-1 study, at 14.1-month median follow-up, teclistamab demonstrated rapid, deep and durable responses, with an overall response rate (ORR) of 63% and median progression-free survival (mPFS) of 11.3 months (see, e.g., Usmani S Z, et al. Lancet 2021; 398:665-674, and Moreau P, et al. New Engl J Med 2022; 387: 495-505, which are incorporated by reference herein).

Patients with relapsed or refractory multiple myeloma (RRMM) are already at increased risk of infection, and bispecific antibodies targeting B-cell maturation antigen (BCMA) may contribute to increased infection risk, due to on-target, off-tumor toxicity. In the MajesTEC-1 clinical study, patients (N=165) received subcutaneous teclistamab 1.5 mg/kg weekly following a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). At a median follow-up of 21.6 months (range 0.26-32.69), infections were reported in 129 patients (78.2%). Overall, grade 3/4 infections occurred in 86 patients (52.1%), most commonly pneumonia (20.6%), COVID-19 (18.8%), sepsis (6.1%), and urinary tract infection (6.1%). Grade 3/4 neutropenia occurred in 65.5% of patients. Thus, there remains a need for optimized dosing regimens of BCMAxCD3 bispecific antibodies with improved safety profiles. The inventors have developed optimized dosing regimens described herein that reduce infection rates in patients, while still achieving rapid, deep and durable clinical responses.

Antibodies of the Present Invention

Any suitable BCMAxCD3 bispecific antibody known to those skilled in the art in view of the present disclosure can be used in the invention.

Various bispecific antibody formats include formats described herein and recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; IgG fusion molecules, wherein full length IgG antibodies are fused to an extra Fab fragment or parts of Fab fragment; Fc fusion molecules, wherein single chain Fv molecules or stabilized diabodies are fused to heavy-chain constant-domains, Fc-regions or parts thereof; Fab fusion molecules, wherein different Fab-fragments are fused together; ScFv- and diabody-based and heavy chain antibodies (e.g., domain antibodies, nanobodies) wherein different single chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g. domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule, or bispecific antibodies generated by arm exchange. Exemplary bispecific formats include dual targeting molecules include Dual Targeting (DT)-Ig (GSK/Domantis), Two-in-one Antibody (Genentech) and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), DuoBody (Genmab), Ts2Ab (MedImmune/AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv/Fc Fusions (Academic Institution), SCORPION (Emergent BioSolutions/Trubion, Zymogenetics/BMS) and Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics), F(ab)2 (Medarex/AMGEN), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB-Celltech), Bispecific T Cell Engager (BITE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), Single-chain Diabody (Academic), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies. Various formats of bispecific antibodies have been described, for example in Chames and Baty (2009) Curr Opin Drug Disc Dev 12: 276 and in Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594.

In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMA binding domains described in WO2017/031104, the entire content of which is incorporated herein by reference. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the CD3 binding domains described in WO2017/031104. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMAxCD3 bispecific antibodies described in WO2017/031104.

In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized or human.

In some embodiments, the bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype. In preferred embodiments, the bispecific antibody is an IgG4 isotype. An exemplary wild-type IgG4 comprises an amino acid sequence of SEQ ID NO: 34.

SEQ ID NO: 34:

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGV

HTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES

KYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQED

PEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK

CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVK

GFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG

NVFSCSVMHEALHNHYTQKSLSLSLGK

The bispecific antibody can be of any allotype. It is expected that allotype has no influence on properties of the bispecific antibodies, such as binding or Fc-mediated effector functions. Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which therapeutic antibodies induce an immune response in the host can be determined in part by the allotype of the antibody (Stickler et al., (2011) Genes and Immunity 12:213-21). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody. Table 2 shows select IgG1, IgG2 and IgG4 allotypes.

TABLE 2

Amino acid residue at position of

diversity (residue numbering: EU Index)

IgG2
IgG4
IgG1

Allotype
189
282
309
422
214
356
358
431

G2m(n)
T
M

G2m(n−)
P
V

G2m(n)/(n−
T
V

nG4m(a)

L
R

G1m(17)

K
E
M
A

G1m(17,1)

K
D
L
A

In some embodiments, the bispecific antibody comprises one or more Fc substitutions that reduces binding of the bispecific antibody to a Fcγ receptor (FcγR) and/or reduces Fc effector functions such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP). The specific substitutions can be made in comparison to the wild-type IgG4 of SEQ ID NO: 34.

Fc positions that can be substituted to reduce binding of the Fc to the activating FcγR and subsequently to reduce effector function are substitutions L234A/L235A on IgG1, V234A/G237A/P238S/H268A/V309L/A330S/P331S on IgG2, F234A/L235A on IgG4, S228P/F234A/L235A on IgG4, N297A on all Ig isotypes, V234A/G237A on IgG2, K214T/E233P/L234V/L235A/G236-deleted/A327G/P331A/D365E/L358M on IgG1, H268Q/V309L/A330S/P331S on IgG2, S267E/L328F on IgG1, L234F/L235E/D265A on IgG1, L234A/L235A/G237A/P238S/H268A/A330S/P331S on IgG1, S228P/F234A/L235A/G237A/P238S on IgG4, and S228P/F234A/L235A/G236-deleted/G237A/P238S on IgG4, wherein residue numbering is according to the EU index.

Fc substitutions that can be used to reduce CDC are a K322A substitution.

Well-known S228P substitution can further be made in IgG4 antibodies to enhance IgG4 stability.

In some embodiments, the bispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

In some embodiments, the one or more asymmetric substitutions is selected from the group consisting of F405L/K409R, wild-type/F405L_R409K, T366Y/F405A, T366W/F405W, F405W/Y407A, T394W/Y407T, T394S/Y407A, T366W/T394S, F405W/T394S and T366W/T366S L368A_Y407V, L351Y_F405A_Y407V/T394W, T366I_K392M_T394W/F405A_Y407V, T366L_K392M_T394W/F405A_Y407V, L351Y_Y407A/T366A_K409F, L351Y_Y407A/T366V_K409F, Y407A/T366A_K409F and T350V_L351Y_F405A_Y407V/T350V_T366L_K392L_T394W.

In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.

In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2.

Tables 3 and 4 provide sequences of an exemplary embodiment of a BCMAxCD3 bispecific antibody, according to the Kabat numbering system.

TABLE 3

Exemplary sequences of a BCMA binding arm

SEQ ID

Region
Sequence
NO:

HCDR1
SGSYFWG
4

HCDR2
SIYYSGITYYNPSLKS
5

HCDR3
HDGAVAGLFDY
6

LCDR1
GGNNIGSKSVH
7

LCDR2
DDSDRPS
8

LCDR3
QVWDSSSDHVV
9

VH
QLQLQESGPGLVKPSETLSLTCTVSGGSISSGS
10

YFWGWIRQPPGKGLEWIGSIYYSGITYYNPSLK

SRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR

HDGAVAGLFDYWGQGTLVTVSS

VL
SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVH
11

WYQQPPGQAPVVVVYDDSDRPSGIPERFSGSNS

GNTATLTISRVEAGDEAVYYCQVWDSSSDHVVF

GGGTKLTVL

HC
QLQLQESGPGLVKPSETLSLTCTVSGGSISSGS
12

YFWGWIRQPPGKGLEWIGSIYYSGITYYNPSLK

SRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR

HDGAVAGLFDYWGQGTLVTVSSASTKGPSVFPL

APCSRSTSESTAALGCLVKDYFPEPVTVSWNSG

ALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG

TKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCP

APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVV

VDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQF

NSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP

SSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQ

VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP

PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVM

HEALHNHYTQKSLSLSLGK

LC
SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVH
13

WYQQPPGQAPVVVVYDDSDRPSGIPERFSGSNS

GNTATLTISRVEAGDEAVYYCQVWDSSSDHVVF

GGGTKLTVLGQPKAAPSVTLFPPSSEELQANKA

TLVCLISDFYPGAVTVAWKGDSSPVKAGVETTT

PSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVT

HEGSTVEKTVAPTECS

TABLE 4

Exemplary sequences of a CD3 binding arm

SEQ

Region
Sequence
ID NO:

HCDR1
TYAMN
14

HCDR2
RIRSKYNNYATYYAASVKG
15

HCDR3
HGNFGNSYVSWFAY
16

LCDR1
RSSTGAVTTSNYAN
17

LCDR2
GTNKRAP
18

LCDR3
ALWYSNLWV
19

VH
EVQLVESGGGLVQPGGSLRLSCAASGFTFNT
20

YAMNWVRQAPGKGLEWVARIRSKYNNYATYY

AASVKGRFTISRDDSKNSLYLQMNSLKTEDT

AVYYCARHGNFGNSYVSWFAYWGQGTLVTVS

S

VL
QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTT
21

SNYANWVQQKPGQAPRGLIGGTNKRAPGTPA

RFSGSLLGGKAALTLSGVQPEDEAEYYCALW

YSNLWVFGGGTKLTVLGQP

HC
EVQLVESGGGLVQPGGSLRLSCAASGFTFNT
22

YAMNWVRQAPGKGLEWVARIRSKYNNYATYY

AASVKGRFTISRDDSKNSLYLQMNSLKTEDT

AVYYCARHGNFGNSYVSWFAYWGQGTLVTVS

SASTKGPSVFPLAPCSRSTSESTAALGCLVK

DYFPEPVTVSWNSGALTSGVHTFPAVLQSSG

LYSLSSVVTVPSSSLGTKTYTCNVDHKPSNT

KVDKRVESKYGPPCPPCPAPEAAGGPSVFLF

PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQ

FNWYVDGVEVHNAKTKPREEQFNSTYRVVSV

LTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI

SKAKGQPREPQVYTLPPSQEEMTKNQVSLTC

LVKGFYPSDIAVEWESNGQPENNYKTTPPVL

DSDGSFLLYSKLTVDKSRWQEGNVFSCSVMH

EALHNHYTQKSLSLSLGK

LC
QTVVTQEPSLTVSPGGTVTLTCRSSTGAVTT
23

SNYANWVQQKPGQAPRGLIGGTNKRAPGTPA

RFSGSLLGGKAALTLSGVQPEDEAEYYCALW

YSNLWVFGGGTKLTVLGQPKAAPSVTLFPPS

SEELQANKATLVCLISDFYPGAVTVAWKADS

SPVKAGVETTTPSKQSNNKYAASSYLSLTPE

QWKSHRSYSCQVTHEGSTVEKTVAPTECS

In some embodiments, the BCMAxCD3 bispecific antibody is CC-93269, BI 836909, JNJ-64007957 (teclistamab), or PF-06863135. In preferred embodiments, the BCMAxCD3 bispecific antibody is teclistamab (also referred to herein as Tec), which has the sequences described in Tables 3 and 4.

Teclistamab and its methods of use are described, for example, in WO 2017/031104, WO 2019/220369 and WO 2021/228783, which are incorporated by reference herein. According to particular embodiments, the BCMAxCD3 bispecific antibody has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of teclistamab.

Additional embodiments of BCMAxCD3 and GPRC5DxCD3 bispecific antibodies that may be used in combination regimens of the present invention are described below.

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG1, an IgG2, an IgG3 or an IgG4 isotype.

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

In certain embodiments, the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).

In certain embodiments, the Fc region of the BCMA-binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

In certain embodiments, the Fc region of the CD3 CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).

In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

Patient Populations with Multiple Myeloma

The BCMAxCD3 bispecific antibodies disclosed herein are for use in treating multiple myeloma in a subject, for example a human subject, wherein the subject is relapsed or refractory to treatment with one or more prior anti-cancer treatments. Relapsed disease means a cancer has come back. Refractory disease means a cancer has not improved with treatment or has stopped responding to treatment.

In some embodiments, the subject is relapsed or refractory to treatment with a therapeutic used to treat multiple myeloma or other hematological malignancies.

In certain embodiments, the subject has had been treated with from 2 to 14 prior lines of therapy.

In certain embodiments, the subject has received at least three prior lines of therapy.

In certain embodiments, the subject has received at least four prior lines of therapy.

In certain embodiments, the subject has received at least five prior lines of therapy (penta-drug exposed).

In certain embodiments, the subject has received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

In certain embodiments, the subject has received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

In particular embodiments, the patients are relapsed or refractory or intolerant to the last line of therapy (LOT); were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy; and had measurable disease.

In some embodiments, the subject has received three anti-cancer therapies prior to administration of the BCMAxCD3 bispecific antibody. In one embodiment, the three prior anti-cancer therapies are a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody. In certain such embodiments, the proteasome inhibitor is bortezomib, carfilzomib or ixazomib, the immunomodulatory drug (IMiD) is lenalidomide, pomalidomide or thalidomide and the anti-CD38 antibody is daratumumab or isatuximab.

In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.

In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.

In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.

In some embodiments, the subject is refractory or relapsed to treatment with one or more treatments or therapies, such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), elotozumab or melphalan, Xpovio® (Selinexor), Venclexta® (Venetoclax), GSK 916, CAR-T therapies, or other BCMA-directed therapies.

Various qualitative and/or quantitative methods can be used to determine relapse or refractory nature of the disease. Symptoms that can be associated are for example a decline or plateau of the well-being of the patient or re-establishment or worsening of various symptoms associated with solid tumors, and/or the spread of cancerous cells in the body from one location to other organs, tissues or cells.

In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, selinexor, venetoclax, lenalinomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.

In one embodiment, the anti-CD38 antibody is daratumumab.

In another embodiment, the anti-CD38 antibody is isatuximab

In some embodiments, the multiple myeloma is a high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to relapse early and have poor prognosis and outcome. Subjects can be classified as having high-risk multiple myeloma is they have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p. In some embodiments, the subject having the high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

The cytogenetic abnormalities can be detected for example by fluorescent in situ hybridization (FISH). In chromosomal translocations, an oncogene is translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. t(4;14)(p16;q32) involves translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain containing protein (MMSET) (also called WHSC1/NSD2), and t(14;16)(q32;q23) involves translocation of the MAF transcription factor C-MAF. Deletion of 17p (dell7p) involves loss of the p53 gene locus.

Chromosomal rearrangements can be identified using well known methods, for example fluorescent in situ hybridization, karyotyping, pulsed field gel electrophoresis, or sequencing.

Bi-Weekly and Monthly Administration of a BCMAxCD3 Bispecific Antibody

The inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that provide improved safety profiles over currently approved regimens while maintaining deep and durable clinical responses over time.

Teclistamab is the first B-cell maturation antigen (BCMA) bispecific antibody approved for the treatment of relapsed/refractory multiple myeloma (RRMM) at a dose of 1.5 mg/kg weekly (QW) given subcutaneously. A less frequent dosing schedule offers added convenience and flexibility to patients, physicians, and caregivers. According to certain embodiments, a dose of 1.5 mg/kg every two weeks (Q2W) given subcutaneously is safe and effective in the treatment of RRMM. According to additional embodiments, a dose of 1.5 mg/kg every four weeks (Q4W) given subcutaneously is safe and effective in the treatment of RRMM.

As used herein, “weight-based” refers to administration of a dose amount that is based on the subject's specific body weight; for example, 3 mg/kg refers to a dose of 3 milligrams of antibody per kilogram of the subject's body weight. Unless otherwise specified herein, when a dose is described in a unit of “mg/kg” or “μg/kg,” weight-based dosing is being employed.

Unless otherwise specified herein, a BCMAxCD3 bispecific antibody, such as teclistamab, is administered on a dosing schedule based on sequential 28-day cycles, for example, Cycle 1 starts on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1, and then Day 1 of Cycle 2 starts the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2, and then Day 1 of Cycle 3 starts the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on.

As used herein “Q4W” means once every four weeks, “Q2W” (also referred to as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also referred to as “weekly”) means once weekly. Q4W is sometimes referred to herein as “monthly” but technically refers to once every 4 weeks or once every 28 days (e.g., in 28-day cycles, a first treatment dose occurs on Day 1 of Cycle 1, a second treatment dose occurs on Day 1 of Cycle 2, etc.). Administration of a treatment dose once weekly (QW) is also referred to herein as a weekly dosing schedule. Administration of a treatment dose once every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. Administration of a treatment dose once every four weeks (Q4W) is also referred to herein as a monthly dosing schedule.

Additional abbreviations used herein include the following: CR, complete response; PR, partial response; Q2W, once every 2 weeks; Q4W, once every 4 weeks; QW, once weekly; RP2D, recommended phase 2 dose; SUD, step-up dose.

As used herein, the RP2D of teclistamab refers to the FDA-approved weight-based regimen for teclistamab monotherapy, based on the MajesTEC-1 clinical study, which includes treatment doses of 1.5 mg/kg teclistamab subcutaneously (SC) administered weekly until disease progression or unacceptable toxicity, wherein the treatment doses are preceded by step-up doses of 0.06 and 0.3 mg/kg. In accordance with embodiments of the present invention, subjects in MajesTEC-1 could switch from weekly to Q2W and subsequently to Q4W dosing as described herein.

According to embodiments of the present invention, methods of treating multiple myeloma are effective in eliciting a clinical response in a subject as determined by International Myeloma Working Group (IMWG) response criteria. According to particular embodiments, the methods of treatment are effective in eliciting a partial response, a very good partial response, a complete response or a stringent complete response, as determined by IMWG response criteria. As used herein, overall response rate (ORR) refers to the percentage of patients in a population that achieve a partial response (PR) or better, i.e., a partial response, very good partial response, complete response or stringent complete response. IMWG criteria for response to Multiple Myeloma treatment are provided in Table A below.

TABLE A

Response
Response Criteria

sCR = stringent
CR as defined below, plus

complete
Normal FLC ratio, and

response
Absence of clonal PCs by immunohistochemistry,

immunofluorescenceª or 2- to 4-color flow cytometry

CR = complete
Negative immunofixation on the serum and urine,

response
and

Disappearance of any soft tissue plasmacytomas,

and

<5% PCs in bone marrow

VGPR = very
Serum and urine M-component detectable by

good partial
immunofixation but not on electrophoresis, or

response
≥90% reduction in serum M-protein plus urine M-

protein <100 mg/24 hours

PR = partial
≥50% reduction of serum M-protein and reduction

response
in 24-hour urinary M-protein by ≥90% or to <200

mg/24 hours

If the serum and urine M-protein are not

measurable, a decrease of ≥50% in the difference

between involved and uninvolved FLC levels is

required in place of the M-protein criteria

If serum and urine M-protein are not measurable,

and serum free light assay is also not measurable,

≥50% reduction in bone marrow PCs is required in

place of M-protein,

provided baseline bone marrow plasma cell

percentage was ≥30%

In addition to the above criteria, if present at

baseline, a ≥50% reduction in the size of soft tissue

plasmacytomas is also required.

CR = complete response;

FLC = free light chain;

IMWG-International Myeloma Working Group;

M-protein-monoclonal paraprotein;

MR = minimal response;

PC = plasma cell;

PD = progressive disease;

PR = partial response;

sCR = stringent complete response;

SD = stable disease;

VGPR = very good partial response

^aPresence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by immunohistochemistry or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of >4:1 or <1:2.

* Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.

IMWG criteria for response to Multiple Myeloma treatment are also described, for example, in Durie et al., Kumar et al. and Rajkumar et al., which are incorporated by reference herein: Durie B G, Harousseau J L, Miguel J S, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9):1467-1473; Kumar S, Paiva B, Anderson K C, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016; 17(8):e328-346; Rajkumar S V, Harousseau J L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical Trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117(18):4691-4695.

Study 64007957MMY1001 (MajesTEC-1) is a single-arm, open-label, multicenter study of teclistamab administered as monotherapy to adult subjects with relapsed or refractory multiple myeloma. Following identification of the proposed RP2D in Phase 1, the anti-myeloma activity and safety of teclistamab were further evaluated in Phase 2 in cohorts of subjects with relapsed or refractory multiple myeloma with unmet medical need. The pivotal population included in the All Treated Analysis Set of MajesTEC-1 comprises 165 subjects (40 treated in Phase 1 and 125 treated in Cohort A of Phase 2).

According to a weekly dosing schedule in MajesTEC-1, teclistamab is administered subcutaneously according to the following weight-based dosing schedule shown in Table B, wherein mg/kg refers to mg of teclistamab per kg of the patient's body weight:

TABLE B

Dosing

Schedule
Day
Dose

Step-up
Day 1
Step-up
0.06 mg/kg

Dosing

dose 1

Schedule
Day 4 ^b
Step-up
0.3 mg/kg

dose 2

Day 7 ^c
First
1.5 mg/kg

treatment

dose

Weekly
One week after
Subsequent
1.5 mg/kg

Dosing
first treatment dose
treatment
once weekly

Schedule
and weekly
doses

thereafter

^bStep-up dose 2 may be given between 2 to 4 days after step-up dose 1 and may be given up to 7 days after step-up dose 1 to allow for resolution of adverse reactions.

^cFirst treatment dose may be given between 2 to 4 days after step-up dose 2 and may be given up to 7 days after step-up dose 2 to allow for resolution of adverse reactions.

According to certain embodiments, patients from the MajesTEC-1 study who transitioned from QW to less frequent Q2W dosing of teclistamab had sustained remission, with a median duration of response of 20.5 months from the date of switch.

According to certain embodiments, a subject begins treatment with teclistamab on a weekly schedule and subsequently switches to a bi-weekly dosing schedule after a period of time. According to an embodiment, a method of treatment comprises administering the BCMAxCD3 bispecific antibody according to the following dosing schedule shown in Table C:

TABLE C

Dosing

Schedule
Day
Dose

Step-up
Day 1
Step-up dose 1
0.06 mg/kg

Dosing
Day 4
Step-up dose 2
0.3 mg/kg

Schedule
Day 7
First treatment dose
1.5 mg/kg

Weekly
One
Subsequent treatment
1.5 mg/kg

Dosing
week after first
doses
once

Schedule
treatment dose

every two weeks

and once every

two weeks

thereafter

According to certain embodiments, the BCMAxCD3 bispecific antibody is administered according to the following schedule shown in TABLE D:

TABLE D

Dosing

Schedule
Day
Dose

All Patients

Step-up
Day 1
Step-up dose 1
0.06 mg/kg

Dosing
Day 4ª
Step-up dose 2
0.3 mg/kg

Schedule
Day 7^b
First treatment dose
1.5 mg/kg

Weekly
One week
Subsequent treatment doses
1.5 mg/kg

Dosing
after first

once weekly

Schedule
treatment

dose and

weekly

thereafter

Patients who have a response for a minimum of 6 months

Biweekly
Consider reducing the dosing frequency to

(every two
1.5 mg/kg every two weeks

weeks)

dosing

schedule

aStep-up dose 2 may be given between 2 to 4 days after step-up dose 1 and may be given up to 7 days after step-up dose 1 to allow for resolution of adverse reactions.

^bFirst treatment dose may be given between 2 to 4 days after step-up dose 2 and may be given up to 7 days after step-up dose 2 to allow for resolution of adverse reactions.

According to certain embodiments, the BCMAxCD3 bispecific antibody is administered according to the following schedule shown in TABLE E:

TABLE E

Dosing schedule
Day
Doseª

All patients

Step-up dosing
Day 1
Step-up dose 1
0.06 mg/kg SC

schedule^b

single dose

Day 3^c
Step-up dose 2
0.3 mg/kg SC

single dose

Day 5^d
First maintenance
1.5 mg/kg SC

dose
single dose

Weekly dosing
One week after first
Subsequent
1.5 mg/kg SC

schedule^b
maintenance dose
maintenance
once weekly

and weekly
doses

thereafter^e

Patients who have a complete response or better for a minimum of 6 months

Biweekly (every
Consider reducing the dosing frequency

two weeks) dosing
two weeksto 1.5 mg/kg SC every

schedulee

^aDose is based on actual body weight and should be administered subcutaneously.

^bSee Table 7 for recommendations on restarting Teclistamab after dose delays.

^cStep-up dose 2 may be given between two to seven days after Step-up dose 1.

^dFirst maintenance dose may be given between two to seven days after Step-up dose 2. This is the first full maintenance dose (1.5 mg/kg).

^eMaintain a minimum of five days between weekly maintenance doses.

According to certain embodiments, the BCMAxCD3 bispecific antibody is administered according to the following schedule shown in TABLE F:

TABLE F

Dosing

Schedule
Day
Dose

All Patients

Step-up
Day 1
Step-up dose 1
0.06 mg/kg

Dosing
Day 4ª
Step-up dose 2
0.3 mg/kg

Schedule
Day 7^b
First treatment dose
1.5 mg/kg

Weekly
One week
Subsequent treatment doses
1.5 mg/kg

Dosing
after first

once weekly

Schedule
treatment

dose and

weekly

thereafter

Patients who have achieved and maintained a complete

response or better for a minimum of 6 months

Biweekly
The dosing frequency may be decreased

(every two
to 1.5 mg/kg every two weeks

weeks)

dosing

schedule

^aStep-up dose 2 may be given between 2 to 4 days after step-up dose 1 and may be given up to 7 days after step-up dose 1 to allow for resolution of adverse reactions.

^bFirst treatment dose may be given between 2 to 4 days after step-up dose 2 and may be given up to 7 days after step-up dose 2 to allow for resolution of adverse reactions.

According to an embodiment, a teclistamab dosing regimen comprises step-up doses of 0.06 mg/kg and 0.3 mg/kg followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity; and, in patients who have a response for a minimum of 6 months, optionally reducing dosing frequency to 1.5 mg/kg every two weeks until disease progression or unacceptable toxicity.

According to an embodiment, a teclistamab dosing regimen comprises step-up doses of 0.06 mg/kg and 0.3 mg/kg followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity; and, in patients that have a complete response or better for a minimum of 6 months, optionally reducing dosing frequency to 1.5 mg/kg every two weeks until disease progression or unacceptable toxicity.

Additional embodiments of dosing regimens of the present invention are described below.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of about 1500 μg/kg.

In certain embodiments, the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) at a treatment dose of about 3000 μg/kg.

In certain embodiments, the method comprises subcutaneously administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) and, if the subject has a complete response or better (i.e., a complete response or stringent complete response according to IMWG 2016 criteria) for a minimum of 6 months, then administering to the subject treatment doses of the BCMAxCD3 bispecific antibody on the bi-weekly dosing schedule (Q2W) (i.e., reducing the frequency of the treatment doses from weekly to bi-weekly after the subject exhibits a complete response or better (complete response or stringent response) for a minimum of 6 months.