Bi-specific antibody engagers for cancer immunotherapy

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Bispecific antibody engagers are engineered fusion proteins.
• They combine nanobodies targeting immunoglobulin kappa light chains with those targeting CTLA-4 or PD-L1.
• Current immune checkpoint blockade typically uses monoclonal antibodies of a single isotype.

Purpose of the Study:

• To evaluate the antitumor activity of bispecific antibody engagers.
• To investigate the mechanism of action involving polyclonal immunoglobulin recruitment.
• To explore strategies for enhancing the efficacy of these engagers.

Main Methods:

• Construction of bispecific antibody engagers targeting immunoglobulin kappa light chains and CTLA-4 or PD-L1.
• Assessment of antitumor activity in the MC38 mouse model of colorectal carcinoma.
• Evaluation of enhanced efficacy through conjugation with cytotoxic drugs (maytansine) or STING agonists.

Main Results:

• Anti-CTLA-4 $$ conjugate demonstrated significant tumor eradication and reduced regulatory T cells in the MC38 model.
• Anti-PD-L1 $$ conjugate showed less efficacy but outperformed similar specificity antibodies.
• Potency of the anti-PD-L1 $$ conjugate was substantially increased with maytansine or a STING agonist.

Conclusions:

• Bispecific antibody engagers can elicit potent antitumor responses by engaging polyclonal immunoglobulins.
• Engaging Fc-mediated functions across all immunoglobulin isotypes presents a promising approach for immune checkpoint blockade.
• Drug conjugation or STING agonism can significantly enhance the therapeutic potential of PD-L1 targeting bispecific engagers.