Human monoclonal antibodies targeting nonoverlapping epitopes on insulin-like growth factor II as a novel type of candidate cancer therapeutics.

Molecular Cancer Therapeutics
Weizao ChenDimiter S Dimitrov

Abstract

Soluble ligands are important targets for therapy of cancers and other diseases. Therapeutic monoclonal antibodies (mAb) against such ligands block their interactions with corresponding receptors but do not enhance their removal from the circulation and can increase their half-lives because of the long half-lives of the antibodies. We have hypothesized that mAbs targeting two or more nonoverlapping epitopes on the same ligand could form oligomeric antibody-ligand complexes that can bind to cells expressing Fc gamma receptors (FcγRs) with high avidity leading to their fast and irreversible removal from the circulation. Insulin-like growth factor II (IGF-II) is an example of such ligands and an important target for human cancer therapy. We identified two mAbs, m610.27 and m630.3, which bound to nonoverlapping epitopes on IGF-II with nanomolar affinity, and generated a bispecific antibody, m660. m660 inhibited the interaction of human IGF-II (hIGF-II) with the human breast cancer cell line MCF-7, hIGF-II-mediated IGF receptor type I and insulin receptor phosphorylation, and cell growth. In the presence of hIGF-II, large complexes of m660 were formed that bound to FcγRII-expressing BJAB cells much more efficiently than the monospec...Continue Reading

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Citations

Nov 10, 2015·Immunopharmacology and Immunotoxicology·Simon KrahHarald Kolmar
Mar 3, 2015·Drug Discovery Today·Roland E Kontermann, Ulrich Brinkmann
Dec 3, 2014·Seminars in Oncology·Ulrich H WeidleUlrich Brinkmann
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May 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Susana FragoAndrew Bassim Hassan
Jan 20, 2017·The Journal of Biological Chemistry·Srinath KasturiranganChangshou Gao
Jun 30, 2019·Current Medicinal Chemistry·Shigao Huang, Qi Zhao
Nov 27, 2019·ACS Combinatorial Science·Eric A MillerHadley D Sikes

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