Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Current IgG isotype monoclonal antibodies (mAbs) are effective anticancer agents but fail to recruit neutrophils.
• IgA mAbs can activate neutrophils via FcαRI but lack NK cell activation and have short half-lives.
• A need exists for novel antibody formats that engage multiple immune effector cells for enhanced cancer therapy.

Purpose of the Study:

• To develop a bispecific antibody format, TrisomAb, combining IgG and IgA functionalities.
• To assess TrisomAb's ability to recruit diverse immune effector cells (NK cells, macrophages, neutrophils) for tumor eradication.
• To evaluate TrisomAb's efficacy, half-life, and potential in preclinical cancer models and patient-derived cells.

Main Methods:

• Development of a bispecific antibody format (TrisomAb) integrating IgG agonistic activity and FcαRI targeting.
• In vitro and in vivo studies to assess effector cell recruitment and tumor cell killing.
• Evaluation of TrisomAb's in vivo half-life and anti-tumor activity in a B16F10gp75 mouse model.
• Assessment of neutrophil-mediated tumor cell killing using colorectal cancer patient samples with anti-EGFR TrisomAb versus IgG anti-EGFR mAb (cetuximab).

Main Results:

• TrisomAb molecules effectively recruited NK cells, macrophages, and neutrophils for tumor cell eradication in vitro and in vivo.
• TrisomAb demonstrated a long in vivo half-life and significantly reduced tumor outgrowth in mice.
• Neutrophils from colorectal cancer patients showed enhanced tumor cell killing with anti-EGFR TrisomAb compared to cetuximab.

Conclusions:

• TrisomAb represents a novel bispecific antibody format capable of engaging multiple immune effector cells for potent anti-tumor activity.
• TrisomAb exhibits favorable pharmacokinetic properties and significant efficacy in preclinical models.
• TrisomAb offers a promising therapeutic alternative for cancer patients who do not respond to conventional IgG mAb therapies.