journal contribution
posted on 2023-03-31, 17:12 authored by Deryk Loo, Ralph F. Alderson, Francine Z. Chen, Ling Huang, Wenjun Zhang, Sergey Gorlatov, Steve Burke, Valentina Ciccarone, Hua Li, Yinhua Yang, Tom Son, Yan Chen, Ann N. Easton, Jonathan C. Li, Jill R. Rillema, Monica Licea, Claudia Fieger, Tony W. Liang, Jennie P. Mather, Scott Koenig, Stanford J. Stewart, Syd Johnson, Ezio Bonvini, Paul A. Moore <p>PDF file, 59KB, Expanded normal tissue IHC analysis of B7-H3 on frozen tissues with MGA271 at optimal staining concentration (4 ug/ml) and at 5x the optimal concentration (20 ug/ml). The optimal staining concentration was determined by titration on the CaKi2 and Hs700T positive control cell lines to determine the lowest MGA271 concentration that yielded the greatest specific staining. (c) = cytoplasmic; (m) = membrane; (c,m) = cytoplasmic plus membrane.</p>
History
ARTICLE ABSTRACT
Purpose: The goal of this research was to harness a monoclonal antibody (mAb) discovery platform to identify cell-surface antigens highly expressed on cancer and develop, through Fc optimization, potent mAb therapies toward these tumor-specific antigens.Experimental Design: Fifty independent mAbs targeting the cell-surface immunoregulatory B7-H3 protein were obtained through independent intact cell-based immunizations using human tissue progenitor cells, cancer cell lines, or cell lines displaying cancer stem cell properties. Binding studies revealed this natively reactive B7-H3 mAb panel to bind a range of independent B7-H3 epitopes. Immunohistochemical analyses showed that a subset displayed strong reactivity to a broad range of human cancers while exhibiting limited binding to normal human tissues. A B7-H3 mAb displaying exquisite tumor/normal differential binding was selected for humanization and incorporation of an Fc domain modified to enhance effector-mediated antitumor function via increased affinity for the activating receptor CD16A and decreased binding to the inhibitory receptor CD32B.Results: MGA271, the resulting engineered anti–B7-H3 mAb, mediates potent antibody-dependent cellular cytotoxicity against a broad range of tumor cell types. Furthermore, in human CD16A-bearing transgenic mice, MGA271 exhibited potent antitumor activity in B7-H3–expressing xenograft models of renal cell and bladder carcinoma. Toxicology studies carried out in cynomolgus monkeys revealed no significant test article-related safety findings.Conclusions: This data supports evaluation of MGA271 clinical utility in B7-H3–expressing cancer, while validating a combination of a nontarget biased approach of intact cell immunizations and immunohistochemistry to identify novel cancer antigens with Fc-based mAb engineering to enable potent antitumor activity. Clin Cancer Res; 18(14); 3834–45. ©2012 AACR.
