A MICA/B GAALIE-mutant antibody elicits potent natural killer cell-driven immunity in solid and hematologic
Ruan Pimenta1, Stefanie Maurer1, Xiaoxuan Zhong1
1Department of Immunology and Immunotherapy, and Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cell Reports. Medicine
|April 18, 2026
Summary
Engineered anti-MICA/B antibodies with enhanced Fc regions show improved cancer immunotherapy potential. These next-generation antibodies effectively inhibit tumor cell metastasis and boost natural killer (NK) cell immunity.
Area of Science:
- Immunology
- Cancer Biology
- Antibody Engineering
Background:
- MICA/B proteins are involved in immune evasion and cancer progression.
- Current anti-MICA/B antibodies are in early clinical trials for cancer immunotherapy.
- Antibody Fc engineering can enhance effector functions and therapeutic efficacy.
Purpose of the Study:
- To engineer an anti-MICA/B antibody (clone 7C6) with an optimized Fc region for enhanced natural killer (NK) cell-mediated immunity.
- To evaluate the efficacy of the engineered antibody (7C6-GAALIE) in preclinical cancer models.
- To establish proof of concept for next-generation anti-MICA/B antibodies in cancer immunotherapy.
Main Methods:
- Engineering of the Fc region of anti-MICA/B antibody 7C6 using GAALIE mutations to increase Fc-activating receptor binding.
- In vitro assessment of MICA/B shedding inhibition and NK cell-effector function induction.
- In vivo evaluation of therapeutic efficacy in metastatic prostate cancer, melanoma, and leukemia mouse models, including Fc gamma receptor-humanized mice.
Main Results:
- 7C6-GAALIE effectively inhibits MICA/B shedding and potently triggers NK cell-mediated cytotoxicity against tumor cells.
- In a metastatic prostate cancer model, 7C6-GAALIE demonstrated superior efficacy in inhibiting metastases compared to wild-type IgG1.
- Consistent therapeutic efficacy was observed with 7C6-GAALIE in melanoma and leukemia models.
Conclusions:
- Fc optimization of anti-MICA/B antibodies can significantly enhance their anti-cancer therapeutic potential.
- The engineered 7C6-GAALIE antibody represents a promising next-generation therapeutic for cancer immunotherapy by boosting NK cell-driven immunity.
- This study validates the strategy of Fc engineering to improve antibody-based cancer treatments.
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