한빛사논문
- 조회3,138
Abstract
Chan Hyuk Kima,1, Jun Y. Axupb,c, Brian R. Lawsona,d, Hwayoung Yunb,c, Virginie Tardifd, Sei Hyun Choib,c, Quan Zhoub,c, Anna Dubrovskab,c, Sandra L. Biroce, Robin Marsdene, Jason Pinstaffe, Vaughn V. Smiderf, and Peter G. Schultza,b,c,1
Departments of bChemistry,
dImmunology and Microbial Science, and
fMolecular Biology and
cThe Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
aCalifornia Institute for Biomedical Research, La Jolla, CA 92037; and
eAmbrx, Inc., La Jolla, CA 92037
Abstract
Bispecific antibodies, which simultaneously target CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, are a promising new approach to the treatment of hormone-refractory prostate cancer. Here we report a site-specific, semisynthetic method for the production of bispecific antibody-like therapeutics in which a derivative of the prostate-specific membrane antigen-binding small molecule DUPA was selectively conjugated to a mutant αCD3 Fab containing the unnatural amino acid, p-acetylphenylalanine, at a defined site. Homogeneous conjugates were generated in excellent yields and had good solubility. The efficacy of the conjugate was optimized by modifying the linker structure, relative binding orientation, and stoichiometry of the ligand. The optimized conjugate showed potent and selective in vitro activity (EC50 ∼100 pM), good serum half-life, and potent in vivo activity in prophylactic and treatment xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.
antibody engineering, immunotherapy
1To whom corresponding may be addressed.
Author contributions: C.H.K. and P.G.S. designed research; C.H.K., J.Y.A., B.R.L., H.Y., V.T., S.H.C., Q.Z., A.D., S.L.B., and R.M. performed research; C.H.K., J.Y.A., H.Y., V.T., S.H.C., Q.Z., S.L.B., R.M., and J.P. contributed new reagents/analytic tools; C.H.K., J.Y.A., B.R.L., H.Y., V.T., S.H.C., Q.Z., A.D., and P.G.S. analyzed data; and C.H.K., B.R.L., V.V.S., and P.G.S. wrote the paper.
논문정보
- Research article
- 2013년 10월 (BRIC 등록일 2013-10-17)
- 국외 연구진
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