Suppression of c-Met-Overexpressing Tumors by a Novel c-Met/CD3 Bispecific Antibody

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Overexpression of the c-Met receptor tyrosine kinase (RTK) is linked to poor prognosis in various cancers, making the HGF/c-Met pathway a key therapeutic target.
• Current antibody-based therapies targeting HGF/c-Met have shown limited clinical success, necessitating alternative strategies like immunotherapy.
• Bispecific antibodies (BsAbs) engaging T cells with tumor cells offer a promising approach for targeting c-Met-overexpressing cancers.

Purpose of the Study:

• To develop and evaluate a novel c-Met/CD3 bispecific antibody (BsAb), BS001, for its anti-tumor efficacy.
• To investigate the mechanisms of action of BS001, including T-cell mediated cytotoxicity and c-Met signaling inhibition.
• To assess the in vivo efficacy of BS001, both as a monotherapy and in combination with immune checkpoint inhibitors.

Main Methods:

• Generation of BS001, a BsAb targeting c-Met and CD3, using a novel platform.
• In vitro evaluation using Western blotting and T-cell mediated killing assays to assess effects on tumor cells.
• In vivo studies using subcutaneous tumor xenograft models (A549, SKOV3) to evaluate anti-tumor effects and combination therapy with PD-L1 inhibitors.

Main Results:

• BS001 demonstrated potent in vitro T-cell mediated killing of tumor cells and inhibited c-Met phosphorylation and downstream signaling.
• In vivo, BS001 inhibited tumor growth in A549 lung cancer xenografts and increased activated tumor-infiltrating lymphocytes.
• Combination therapy of BS001 with PD-L1 antibodies (Atezolizumab, Pembrolizumab) resulted in superior tumor inhibition and prevented tumor recurrence in a significant proportion of treated mice.

Conclusions:

• The c-Met/CD3 bispecific antibody BS001 exhibits significant anti-tumor activity through dual mechanisms: T-cell mediated tumor cell lysis and direct inhibition of c-Met signaling.
• BS001 demonstrates potent efficacy in preclinical models, supporting its potential as a novel cancer immunotherapy.
• Combination strategies involving BS001 may overcome limitations of current therapies and offer improved outcomes for patients with c-Met-overexpressing cancers.