Journal ArticleDOI
Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies.
Gail D. Lewis,I S Figari,Brian M. Fendly,Wai Lee Wong,Paul Carter,Cornelia M. Gorman,H M Shepard +6 more
TLDR
The engineered monoclonal antibodies built up in combination with human peripheral blood mononuclear cells elicited antibody-dependent cytotoxic responses in accordance with the level of p185HER2 expression, expanding the potential target population for antibody-mediated therapy of human cancers characterized by the overexpression of p 185HER2.Abstract:
The HER2 protooncogene encodes a receptor tyrosine kinase, p185HER2. The overexpression of p185HER2 has been associated with a worsened prognosis in certain human cancers. In the present work we have screened a variety of different tumor cell lines for p185HER2 expression using both enzyme-linked immunosorbent and fluorescence-activated cell sorting assays employing murine monoclonal antibodies directed against the extracellular domain of the receptor. Increased levels of p185HER2 were found in breast (5/9), ovarian (1/6), stomach (2/3) and colorectal (5/16) carcinomas, whereas all kidney and submaxillary adenocarcinoma cell lines tested were negative. Some monoclonal antibodies directed against the extracellular domain of p185HER2 inhibited growth in monolayer culture of breast and ovarian tumor cell lines overexpressing p185HER2, but had no effect on the growth of colon or gastric adenocarcinomas expressing increased levels of this receptor. The most potent growth-inhibitory anti-p185HER2 monoclonal antibody in monolayer culture, designated mumAb 4D5 (a murine IgG1κ antibody), was also tested in soft-agar growth assays for activity against p185HER2-overexpressing tumor cell lines of each type, with similar results. In order to increase the spectrum of tumor types potentially susceptible to monoclonal antibody-mediated anti-p185HER2 therapies, to decrease potential immunogenicity issues with the use of murine monoclonal antibodies for human therapy, and to provide the potential for antibody-mediated cytotoxic activity, a mouse/human chimeric 4D5 (chmAb 4D5) and a “humanized” 4D5 (rhu)mAb 4D5 HER2 antibody were constructed. Both engineered antibodies, in combination with human peripheral blood mononuclear cells, elicited antibody-dependent cytotoxic responses in accordance with the level of p185HER2 expression. Since this cytotoxic activity is independent of sensitivity to mumAb 4D5, the engineered monoclonal antibodies expand the potential target population for antibody-mediated therapy of human cancers characterized by the overexpression of p185HER2.read more
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Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets.
TL;DR: It is demonstrated that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcγRIIB.
Journal ArticleDOI
The ErbB signaling network: receptor heterodimerization in development and cancer
TL;DR: The role of ErbB receptors as normal signal transducers and their contribution to the process of malignant transformation during tumor development are concentrated on.
Journal ArticleDOI
The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity.
Toyohide Shinkawa,Kazuyasu Nakamura,Naoko Yamane,Emi Shoji-Hosaka,Yutaka Kanda,Mikiko Sakurada,Kazuhisa Uchida,Hideharu Anazawa,Mitsuo Satoh,Motoo Yamasaki,Nobuo Hanai,Kenya Shitara +11 more
TL;DR: The results indicate that the lack of fucosylation of IgG1 has the most critical role in enhancement of ADCC, although several reports have suggested the importance of Gal or bisecting GlcNAc and provide important information to produce the effective therapeutic antibody.
Journal ArticleDOI
Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.
José Baselga,Debasish Tripathy,John Mendelsohn,S. Baughman,Christopher C. Benz,L. Dantis,Nancy Sklarin,Andrew D. Seidman,Clifford A. Hudis,J. Moore,Paul Peter Rosen,T. Twaddell,I. C. Henderson,Larry Norton +13 more
TL;DR: RhuMAb HER2 is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior therapy and justifies further evaluation of this agent.
Journal ArticleDOI
Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate
Gail Lewis Phillips,Guangmin Li,Debra L. Dugger,Lisa Crocker,Kathryn Parsons,Elaine Mai,Walter A. Blattler,John M. Lambert,Ravi V. J. Chari,Robert J. Lutz,Wai Lee T. Wong,Frederic S. Jacobson,Hartmut Koeppen,Ralph H. Schwall,Sara R. Kenkare-Mitra,Susan D. Spencer,Mark X. Sliwkowski +16 more
TL;DR: In vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers are determined andtrastuzuab-MCC-DM1 shows greater activity compared with nonconjugated trastumab while maintaining selectivity for HER2-overexpressing tumor cells.
References
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Journal ArticleDOI
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Journal ArticleDOI
Humanization of an anti-p185HER2 antibody for human cancer therapy.
Paul Carter,L. G. Presta,Cornelia M. Gorman,John B. Ridgway,Dennis J. Henner,Wai Lee Wong,A. M. Rowland,Claire Kotts,M. E. Carver,H M Shepard +9 more
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