Potent Apoptosis Induction by a Novel Trispecific B7-H3xCD16xTIGIT 2+1 Common Light Chain Natural Killer Cell Engager

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Natural killer (NK) cells are increasingly recognized for their therapeutic potential in immunotherapy due to their potent anti-tumor activity and safety.
• NK cell function is regulated by a balance of activating and inhibitory receptors, presenting targets for antibody-mediated modulation.
• B7-H3 and TIGIT are key receptors involved in NK cell regulation and cancer immune evasion.

Purpose of the Study:

• To isolate novel monoclonal antibodies targeting B7-H3 and TIGIT.
• To engineer a potent NK-engaging molecule by combining these antibodies with a CD16-binding fragment.
• To evaluate the efficacy of the engineered molecule in inducing cancer cell apoptosis.

Main Methods:

• Utilized a common light chain (cLC)-based yeast surface display (YSD) screening method to identify monoclonal antibodies.
• Generated chicken-derived antibodies with high affinity (single- to low-double-digit nanomolar) for B7-H3 and TIGIT.
• Constructed a 2+1 format bispecific antibody (B7-H3xCD16xTIGIT) by integrating a CD16-binding Fab fragment.

Main Results:

• Successfully isolated novel monoclonal antibodies targeting B7-H3 and TIGIT with high affinity.
• The B7-H3xCD16xTIGIT construct demonstrated potent induction of apoptosis in cancer cells.
• The engineered molecule effectively leverages NK cell cytotoxic mechanisms.

Conclusions:

• The TIGIT NK checkpoint, when combined with activating receptors like B7-H3 and CD16, offers a promising strategy for enhancing anti-tumor cytotoxic activity.
• This bispecific antibody approach represents a significant advancement in NK cell-based immunotherapy.
• Further development of such engineered NK-engaging molecules holds potential for effective cancer treatment.