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Pan‐HER biologics (Hermodulins) for the treatment of cancer
Author(s) -
Maneval Daniel C.,
Jin Pei,
Shepard H. Michael
Publication year - 2008
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.20277
Subject(s) - cetuximab , erlotinib , epidermal growth factor receptor , trastuzumab , cancer research , cancer , signal transduction , biology , epidermal growth factor , receptor , drug development , pharmacology , drug , microbiology and biotechnology , breast cancer , colorectal cancer , biochemistry , genetics
Abstract The four members of the human epidermal growth factor receptor (HER) family and their cognate ligands combine in a complex network to play key roles in normal growth and development. Abnormal expression, mutation, or altered signaling of HER proteins has been linked to the pathogenesis of multiple human malignancies. Clinical benefit for patients with solid tumors of the breast, colon, lung, pancreas, or head and neck has been proven for targeted antagonists directed at a single receptor in the HER family (e.g., trastuzumab, cetuximab, erlotinib). Although effective, tumor resistance to these single‐targeted drugs frequently develops, and efficacy is not as broad as was initially predicted. Redundant signaling of other HER family members provides a likely mechanism for diminished drug activity. An alternative approach to inhibit HER‐mediated tumor growth is to sequester stimulating EGF‐like growth factors with a “ligand‐trap” strategy. Hermodulins are fusion proteins that link the extracellular ligand binding domains of HER family members to the Fc region of human IgG. Data with RB200, a first‐generation Hermodulin, demonstrate effective binding of EGFR and HER3 ligands (e.g., EGF, TGF‐α, NRG1‐β1) and show anti‐tumor activity in preclinical models. An optimized molecule, RB242, has been designed that combines single amino acid changes in the extracellular domains of the EGFR and HER3 domains. Preclinical studies with RB242 are ongoing to enable testing of the pan‐HER ligand‐trap hypothesis in Phase I investigation. Drug Dev Res 69:472–479, 2008. © 2008 Wiley‐Liss, Inc.