Targeting MICA/B with cytotoxic therapeutic antibodies leads to tumor control

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• MICA and MICB are stress-induced proteins expressed on solid tumors, binding to the NKG2D receptor on cytotoxic lymphocytes.
• Their tumor-specific expression and immunogenicity make MICA and MICB attractive targets for cancer therapy.
• High polymorphism in MICA and MICB necessitates cross-reactive therapeutic agents.

Purpose of the Study:

• To develop novel therapeutic antibodies targeting MICA and MICB.
• To evaluate the efficacy of antibody-drug conjugates (ADCs) for solid tumor treatment.

Main Methods:

• Generation of cross-reactive anti-MICA and MICB monoclonal antibodies (mAbs).
• Engineering of a human IgG1 Fc variant antibody, MICAB1.
• In vitro assessment of antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP).
• In vivo efficacy studies using solid tumor models, including patient-derived xenografts (PDX) and MICAgen transgenic mice.

Main Results:

• The MICAB1 mAb showed potent in vitro ADCC and ADCP against MICA/B-expressing tumor cells.
• MICAB1-ADC demonstrated optimal tumor control in various solid tumor models.
• Effective targeting was observed in both PDX and carcinogen-induced tumors in immunocompetent mice.

Conclusions:

• MICA and MICB are validated as promising targets for antibody-drug conjugate-based cancer immunotherapy.
• MICAB1-ADC represents a potential therapeutic strategy for solid tumors expressing MICA/B.
• Further development of MICA/B-targeted ADCs warrants investigation.