Claims
- 1. A method for optimizing at least one physico-chemical property of an antibody, said method executed by a computer under the control of a program, said computer including a memory for storing said program, said method comprising the steps of:
a. receiving a template antibody structure; b. selecting at least one variable positions which belong to said template antibody structure; c. selecting at least one amino acids to be considered at said variable positions; d. analyzing the interaction of each of said amino acids at each variable position with at least part of the remainder of said antibody, including said amino acids at other variable positions; and e. identifying a set of at least one antibody sequence with at least one optimized physico-chemical property.
- 2. A method according to claim 1, wherein at least one of the optimized physico-chemical properties is selected from the group consisting of stability, solubility, and antigen binding affinity.
- 3. A method according to claim 2, wherein at least one of the optimized physico-chemical properties is stability.
- 4. A method according to claim 3, wherein the stabilized portion of said antibody is selected from the group consisting of a domain and an interface between domains.
- 5. A method according to claim 4, wherein the stabilized portion of said antibody is a domain.
- 6. A method according to claim 4, wherein the stabilized portion of said antibody is an interface between domains.
- 7. A method according to claim 2, wherein the physico-chemical property is solubility.
- 8. A method according to claim 7, wherein at least one antibody sequence possesses an increase in polar character.
- 9. A method according to claim 7, wherein said selecting step further comprises selecting at least one nonpolar amino acid and substituting said nonpolar amino acid with a polar amino acid.
- 10. A method according to claim 7, wherein said selecting step further comprises altering the pI of the antibody.
- 11. A method according to claim 2, wherein at least one of the optimized physico-chemical properties is antigen binding affinity.
- 12. A method according to claim 11, wherein at least one of said variable positions is located in a framework region of the antibody.
- 13. A method according to claim 11, wherein at least one of said variable positions is located in a complementarity determining region (CDR) of the antibody.
- 14. A method according to claim 1, wherein each of said amino acids at each of said variable positions are represented as a group of potential rotamers.
- 15. A method according to claim 1, wherein at least two variable positions are selected and at least two amino acids are considered at each variable position.
- 16. A method according to claim 1, wherein said analyzing step further comprises a computational step utilizing at least two of the energy terms selected from the group consisting of van der Waals, electrostatics, hydrogen bonds and solvation.
- 17. A method according to claim 1, wherein said variable positions are chosen based on their level of variability in a set of aligned antibody sequences.
- 18. A method according to claim 1, wherein one said amino acids are chosen from a list of amino acids which occur at said position or positions in a set of aligned antibody sequences.
- 19. A method according to claim 1, wherein said analyzing step includes a Protein Design Automation program.
- 20. A method according to claim 1, wherein said analyzing step includes a Sequence Prediction Algorithm program.
- 21. A method according to claim 1, wherein said antibody is selected from the group consisting of a full-length antibody and an antibody fragment.
- 22. A method according to claim 1, wherein said antibody sequence is substantially encoded by at least one mammalian antibody gene.
- 23. A method according to claim 1, wherein said antibody is selected from the group consisting of a fully human antibody, a humanized antibody, a chimeric antibody, and an engineered antibody.
- 24. A method according to claim 1, further comprising f) generating a library from said set of at least one antibody sequence.
- 25. A method according to claim 24 wherein said library is a computational library.
- 26. A method according to claim 24 wherein said library is generated experimentally.
- 27. A method according to claim 24 further comprising g) experimentally screening said library.
- 28. A method according to claim 27, wherein said library is screened using at least one selection method.
- 29. A method according to claim 25, wherein said library is screened using at least one selection method selected from the group consisting of: phage display methods, cell surface display, in vitro display, and cytometric screening.
- 30. A method according to claim 25, wherein said selection method is a directed evolution method.
- 31. An antibody sequence from said library of claim 24.
- 32. An antibody sequence according to claim 28, wherein said antibody sequence is substantially encoded by a mammalian antibody gene.
- 33. An antibody identified from said screening of claim 24.
- 34. An antibody to claim according to claim 33, wherein said antibody is a full-length antibody or an antibody fragment.
- 35. An antibody according to claim 33, wherein said antibody is selected from the group consisting of a fully human antibody, a humanized antibody, a chimeric antibody, and an engineered antibody.
- 36. A method of treating a patient in need of said treatment, comprising administering an antibody of claim 28 to said patient.
Parent Case Info
[0001] This application claims the benefit of the filing date of Ser. No. 60/360,843, filed Mar. 1, 2002 and Ser. No. 60/384,197, filed May 29, 2002, both of which are expressly incorporated by reference in their entirety.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60360843 |
Mar 2002 |
US |
|
60384197 |
May 2002 |
US |