Nanobody-based bispecific antibody engagers targeting CTLA-4 or PD-L1 for cancer immunotherapy
Year: 2025
Type: article
Abstract: Bispecific antibody engagers are fusion proteins composed of a nanobody that recognizes immunoglobulin kappa light chains (VHHkappa) and a nanobody that recognizes either CTLA-4 or PD-L1. These fusions show strong antitumor activity in mice through recruitment of polyclonal immunoglobulins independently of specificity or isotype. In the MC38 mouse model of colorectal carcinoma, the anti-CTLA-4 VHH-VHHkappa conjugate eradicates tumors and reduces the number of intratumoral regulatory T cells. The anti-PD-L1 VHH-VHHkappa conjugate is less effective in the MC38 model, whilst still outperforming an antibody of similar specificity. The potency of the anti-PD-L1 VHH-VHHkappa conjugate was strongly enhanced by installation of the cytotoxic drug maytansine or a STING agonist. The ability of such fusions to engage the Fc-mediated functions of all immunoglobulin isotypes is an appealing strategy to further improve on the efficacy of immune checkpoint blockade, commonly delivered as a monoclonal immunoglobulin of a single defined isotype. *Xin Liu, Camille Le Gall, and Ryan K. Alexander contributed equally.
Source: Nature Biomedical Engineering
Institutions: Boston Children's Hospital, Harvard University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4412470476