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: Bi- and multispecific antibody derivatives (bsAbs) can be considered as the next generation of targeted biologics for cancer therapy. The general concept of bsAbs is a physical connection of recombinant antibody-derived entities with at least two binding specificities. This generates bsAbs that bind at least two antigens or epitopes, thus altering their binding functionalities and specificities in comparison to "normal" antibodies. Most bsAbs are produced as recombinant proteins, either as large IgG-like proteins that contain Fc regions, or as smaller entities with multiple antigen-binding regions but without Fc. Application of bsAbs in experimental cancer therapy currently includes molecules that bind different cell surface proteins to achieve more complete blockage of proliferative or angiogenesis-associated pathways. This approach of blocking more than one pathway component, or to simultaneously hit complementing pathways, also may limit potential escape mechanisms of cancer cells. BsAbs also are applied in the clinic as vehicles to deliver immune effector cells and/or cytokines to tumors. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.Seminars in Oncology 08/2014; 41(5):653–660. · 3.94 Impact Factor
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ABSTRACT: Type 1 insulin-like growth factor receptor (IGF1R) signalling plays a critical role in normal cell growth, and in cancer development and progression. IGF1R and the insulin-like growth factors 1 and 2 (IGF1 and IGF2) are involved in various aspects of the malignant phenotype, suggesting that IGF1R is a potential target for cancer therapy. IGF1R is particularly important in the establishment and maintenance of the transformed phenotype, in mediating proliferation, and for the survival of tumour cells with anchorage-independent growth. IGF1R also exerts antiapoptotic activity and has a substantial influence on the control of the cell and body size. This property enables transformed cells to form macroscopic tumours and to survive the process of detachment required for metastasis. Pharmaceutical companies are investigating molecules that target IGF1R, including specific low molecular weight tyrosine kinase inhibitors and monoclonal antibodies, both of which possess various advantages and display different activity profiles. This review article focuses on the preclinical and clinical development of low molecular weight IGF1R tyrosine kinase inhibitors. It is critical to pursue a thorough molecular analysis of the metabolic activity of IGF1R to avoid possible side-effects of its inhibition.The Journal of international medical research 03/2013; · 1.10 Impact Factor
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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; · 4.65 Impact Factor