Bispecific small molecule–antibody conjugate targeting prostate cancer

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 o...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (44), p.17796-17801
Main Authors: Kim, Chan Hyuk, Axup, Jun Y., Lawson, Brian R., Yun, Hwayoung, Tardif, Virginie, Choi, Sei Hyun, Zhou, Quan, Dubrovska, Anna, Biroc, Sandra L., Marsden, Robin, Pinstaff, Jason, Smider, Vaughn V., Schultz, Peter G.
Format: Article
Language:English
Subjects:
Amino acids
Animals
Antibodies
Antigens
Biological Sciences
Bispecific antibodies
CD3 Complex - immunology
Cytotoxicity
Drug Discovery - methods
Heterografts - immunology
Humans
Immunoglobulin Fab Fragments - immunology
Immunoglobulin Fab Fragments - therapeutic use
Immunotherapy - methods
Leukocytes, Mononuclear
Ligands
Male
Mice
Molecules
Prostate cancer
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - immunology
Protein Engineering
T lymphocytes
Tumors
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Summary: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 (EC ₅₀ ∼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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1316026110