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Updated: May 22, 2026
Analyzing Tumor and Tissue Distribution of Target Antigen Specific Therapeutic Antibody
Published on: May 16, 2020
Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity
Deryk Loo1, Ralph F Alderson, Francine Z Chen
1MacroGenics, Inc., South San Francisco, CA, USA.
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.
Insights
Researchers developed MGA271, a potent monoclonal antibody (mAb) therapy targeting B7-H3. This engineered anti-B7-H3 mAb shows strong antitumor activity in preclinical models and minimal toxicity, supporting clinical evaluation for B7-H3-expressing cancers.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Monoclonal antibodies (mAbs) are crucial in cancer therapy.
- Identifying tumor-specific antigens is key for targeted mAb development.
- Fc optimization enhances mAb effector functions for improved antitumor activity.
Purpose of the Study:
- To discover cell-surface antigens highly expressed on cancer using a mAb discovery platform.
- To develop potent mAb therapies targeting tumor-specific antigens through Fc optimization.
- To engineer an anti-B7-H3 mAb with enhanced effector functions and tumor-specific binding.
Main Methods:
- Generated 50 anti-B7-H3 mAbs via intact cell-based immunizations.
- Selected mAbs based on binding affinity, tumor reactivity, and normal tissue sparing via immunohistochemistry.
- Engineered a selected mAb (MGA271) with Fc modifications for enhanced CD16A binding and reduced CD32B binding.
Main Results:
- MGA271 demonstrated potent antibody-dependent cellular cytotoxicity against various tumor cell types.
- MGA271 showed significant antitumor activity in B7-H3-expressing renal cell and bladder carcinoma xenograft models in mice.
- Toxicology studies in non-human primates revealed no significant safety concerns.
Conclusions:
- MGA271 is a promising therapeutic candidate for B7-H3-expressing cancers.
- The study validates a combined approach of cell-based immunization and immunohistochemistry for novel cancer antigen discovery.
- Fc-based mAb engineering is effective in creating potent antitumor therapies.
