Liu, Le Gall, Alexander, et al. developed bivalent nanobody conjugates targeting CTLA-4 or PD-L1, which could be loaded with small-molecule drug payloads. In mouse tumor models, the nanobody conjugates trafficked to the tumor and inhibited tumor growth. To improve the antitumor effects of the PD-L1 conjugate, maytansine and a STING agonist were assessed as payloads, which increased local T cell activation, reduced tumor growth, and improved survival.
ABSTRACT: As immune checkpoint blockade induces durable responses in only a subset of patients, more effective immunotherapies are needed. Here we present bispecific antibody engagers, fusion proteins composed of a nanobody that recognizes immunoglobulin kappa light chains (VHH(kappa)) and a nanobody that recognizes either CTLA-4 or PD-L1. These fusions show strong antitumour activity in mice through recruitment of polyclonal immunoglobulins independently of specificity or isotype. The anti-CTLA-4 VHH-VHH(kappa) conjugate demonstrates superior antitumour activity compared with the conventional monoclonal anti-CTLA-4 antibody and reduces the number of intratumoural regulatory T cells in a mouse model of colorectal carcinoma. The anti-PD-L1 VHH-VHH(kappa) conjugate is less effective in the colorectal carcinoma model while still outperforming a conventional antibody of similar specificity. The potency of the anti-PD-L1 VHH-VHH(kappa) conjugate was 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.
