Development of an Fc-Enhanced Anti–B7-H3 Monoclonal Antibody with Potent Antitumor Activity

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 effectormediated 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.

PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

“…Interestingly, while the checkpoint genes PD-L2 and LAG3 were both more highly expressed in PD-L1-positive tumors, another checkpoint gene, CD276, was more highly expressed in PD-L1-negative tumors. CD276 is the target of the anticheckpoint drug MGA271 (28) currently undergoing a phase I clinical trial in combination with ipilimumab. Low-level or downregulated MHC-I antigen presentation may be another feature of PD-L1-negative specimens.…”

B7-H3 silencing inhibits tumor progression of mantle cell lymphoma and enhances chemosensitivity

“…With the development of B7-H3 targeted therapeutics, a range of anti-B7-H3 antibodies are under research and some have entered clinical trial for B7-H3-expressing cancers, such as MGA271 (35). In our study, we treated the Maver and Z138 xenograft models with the plasmid of B7-H3 shRNA combined with R and/or Ben, and found that the inhibition rates of tumor growth were dramatically higher than in the relative non-targeted control plasmid combining chemotherapy groups.…”

Cancer Immunotherapy Based on the Blockade of Immune Checkpoints

“…Как правило, такая нарушенная экспрессия связана с неблагопри-ятным прогнозом для пациентов [4,68,78,88]. Основываясь на данных, полученных с примене-нием мышиных моделей, начаты работы по соз-данию блокирующих агентов против B7-H3 [36] и B7-H4 [16], а также анализ их противоопухоле-вой активности in vivo.…”