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Ref Type Journal Article
PMID (21149738)
Authors Doppalapudi VR, Huang J, Liu D, Jin P, Liu B, Li L, Desharnais J, Hagen C, Levin NJ, Shields MJ, Parish M, Murphy RE, Del Rosario J, Oates BD, Lai JY, Matin MJ, Ainekulu Z, Bhat A, Bradshaw CW, Woodnutt G, Lerner RA, Lappe RW
Title Chemical generation of bispecific antibodies.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 107
Issue 52
Date 2010 Dec 28
URL
Abstract Text Bispecific antibodies (BsAbs) are regarded as promising therapeutic agents due to their ability to simultaneously bind two different antigens. Several bispecific modalities have been developed, but their utility is limited due to problems with stability and manufacturing complexity. Here we report a versatile technology, based on a scaffold antibody and pharmacophore peptide heterodimers, that enables rapid generation and chemical optimization of bispecific antibodies, which are termed bispecific CovX-Bodies. Two different peptides are joined together using a branched azetidinone linker and fused to the scaffold antibody under mild conditions in a site-specific manner. Whereas the pharmacophores are responsible for functional activities, the antibody scaffold imparts long half-life and Ig-like distribution. The pharmacophores can be chemically optimized or replaced with other pharmacophores to generate optimized or unique bispecific antibodies. As a prototype, we developed a bispecific antibody that binds both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) simultaneously, inhibits their function, shows efficacy in tumor xenograft studies, and greatly augments the antitumor effects of standard chemotherapy. This unique antiangiogenic bispecific antibody is in phase-1 clinical trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CVX-241 CVX-241 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CVX-241 CVX-241 is a peptide-antibody fusion protein that targets both Angiopoetin-2 (Ang2) and Vegf, potentially resulted in decreased tumor growth (PMID: 21149738).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colon adenocarcinoma not applicable CVX-241 + Irinotecan Preclinical - Cell line xenograft Actionable In a preclinical study, treatment with the combination of CVX-241 and Camptosaur (irinotecan) resulted in increased tumor growth inhibition compared to either agent alone in a colon adenoarcinoma cell line xenograft model (PMID: 21149738). 21149738
Unknown unknown breast carcinoma not applicable CVX-241 Preclinical - Cell line xenograft Actionable In a preclinical study, CVX-241 inhibited tumor growth in a breast carcinoma cell line xenograft model (PMID: 21149738). 21149738
Unknown unknown skin carcinoma not applicable CVX-241 Preclinical - Cell line xenograft Actionable In a preclinical study, CVX-241 inhibited tumor growth in a skin carcinoma cell line xenograft model (PMID: 21149738). 21149738
Unknown unknown colon adenocarcinoma not applicable CVX-241 Preclinical - Cell line xenograft Actionable In a preclinical study, CVX-241 decreased Ang2 and phosphorylated and total Vegfr2 levels and inhibited tumor growth in a colon adenocarcinoma cell line xenograft model (PMID: 21149738). 21149738