Research Project
6932141
DESCRIPTION (provided by applicant): Antibodies are the most rapidly expanding class of drugs to treat human disease, including cancer. However, current antibody therapies in oncology are seldom, if ever, curative. Thus there remains a need to improve the response rate and duration for anti-cancer antibodies. Conjugation to cytotoxic drugs is one of the most promising ways to enhance the antitumor efficacy of antibodies. Significant progress has been made in optimizing the chemistry of drug conjugates, whereas their antibody component remains to be optimized. E.g., the chimeric anti-CD30 antibody, cAC10, has been conjugated via plasma stable peptide linkers to the potent cytotoxic drug, monomethyl auristatin E (MMAE). This culminated in efficacy of cAC10 IgG-MMAE in SCID mouse xenograft models of anaplastic large cell lymphoma (ALCL) and Hodgkin's disease at doses well below the maximally tolerated dose. This application builds upon these earlier studies with cAC10 IgG-MMAE and includes key personnel (Drs. P. Senter and J. Francisco), instrumental to the prior work. A vexing challenge with antibody drug conjugates is toxicity due to release of drug at non-tumor sites. Unfortunately, drug liberation following conjugate catabolism appears to be the unavoidable ultimate in vivo fate of IgG drug conjugates. The use of antibody fragments for drug conjugation offers a potential way to circumvent the catabolic fate of IgG drug conjugates. This reflects that antibody fragments are eliminated rapidly and primarily by renal filtration. If antibody fragment conjugates are excreted with drug still attached, this will lessen the exposure of non-tumor sites to free drug and may reduce the observed toxicity. This proposal tests the feasibility of using antibody fragment drug conjugates for cancer therapy. Diabody, minibody and scFv-Fc antibody fragments of the anti-CD30 MAb, AC10, will be prepared and conjugated to MMAE. These antibody fragment drug conjugates plus control conjugates will be compared in their in vitro antitumor activities. Potent antibody conjugates will be compared in their biodistribution and efficacy in a SCID mouse xenograft model of ALCL as well as their pharmacokinetics and toxicity in SCID mice. Robust in vivo efficacy with any antibody fragment drug conjugate with acceptable toxicities would provide the foundation for a future SBIR Phase II application. Our ultimate goal is to use an optimized antibody fragment drug conjugate to treat CD30 positive hematologic malignancies such as Hodgkin's disease, ALCL and cutaneous T cell lymphoma. Advances made with anti-CD30 antibody fragment drug conjugates are anticipated to be broadly applicable to other antibodies with therapeutic potential.
