Human monoclonal antibodies targeting nonoverlapping epitopes on insulin-like growth factor II as a novel type of candidate cancer therapeutics.
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 monospecific antibody-hIGF-II complexes and were presumably phagocytosed by phorbol 12-myristate 13-acetate-stimulated macrophage-like U937 cells. A mixture of m610.27 and m630.3 exhibited similar properties. To our knowledge, these mAbs are the first reported to target nonoverlapping epitopes on a cancer-related ligand and could represent a novel class of candidate therapeutics against cancers. This approach could also be used to irreversibly eliminate other disease-related soluble ligands.
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ABSTRACT: Soluble forms of the human immunodeficiency virus type 1 (HIV-1) primary receptor CD4 (sCD4) have been extensively characterized for a quarter of a century as promising HIV-1 inhibitors but have not been clinically successful. By combining a protein cavity-filling strategy and the power of library technology, we identified an engineered cavity-altered single-domain sCD4 (mD1.22) with a unique combination of excellent properties including broad and potent neutralizing activity, high specificity, stability, solubility, and affinity for the HIV-1 envelope glycoprotein gp120, and small molecular size. To further improve its neutralizing potency and breadth, we generated bispecific multivalent fusion proteins of mD1.22 with another potent HIV-1 inhibitor - an antibody domain (m36.4) targeting the coreceptor-binding site on gp120. The fusion proteins neutralized all HIV-1 isolates tested with potency about 10-, 50-, and 200-fold higher than that of the broadly neutralizing antibody VRC01, the US FDA-approved peptide inhibitor T20, and the clinically tested sCD4-Fc fusion protein CD4-Ig, respectively. In addition, they exhibited higher stability and specificity, and lower aggregation propensity than CD4-Ig. Therefore, mD1.22 and related fusion proteins could be potentially useful for HIV-1 prevention and therapy including eradication of the virus.Journal of Virology 11/2013; · 5.08 Impact Factor
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ABSTRACT: The insulin-like growth factor I (IGF-I) receptor (IGF-1R) is overexpressed in most human neoplasms tested so far. Many tumors in young patients produce high levels of the IGF-1R ligands, IGF-I and IGF-II. Given the complexity of the IGF signaling pathway, its complete inhibition may require combination therapies with antibodies targeting both IGF-1R and IGF-II.Oncoimmunology. 11/2012; 1(8):1390-1391.
- Seminars in Oncology 08/2014; 41(5):653–660. · 4.33 Impact Factor