Potency-optimized CD28-activating bispecific antibody for the targeted treatment of Nectin-4 positive cancers
Year: 2025
Type: article
Abstract: Background T-cell costimulation is crucial for an effective and sustained antitumor immune response, and inadequate expression of costimulatory ligands within tumors can impair T-cell function. Bispecific antibodies (bsAbs) targeting a tumor-associated antigen and the T-cell costimulatory receptor CD28 represent a novel class of immune-stimulatory therapeutics designed to enhance antitumor immune responses by selectively delivering T-cell costimulation directly to the tumor microenvironment. This approach holds the potential to improve the survival, proliferation, and cytotoxic function of antitumor T cells while minimizing the risk of systemic immune activation. Urothelial cancer (UC) is associated with significant morbidity and mortality worldwide, particularly in advanced disease settings. Nectin-4, a membrane protein highly expressed in UC with limited expression in healthy tissues, presents a compelling target for therapeutic intervention. Methods Using our proprietary high-throughput antibody discovery pipeline, we identified a panel of novel antibodies with a range of affinities for CD28 and Nectin-4 and successfully engineered them as bsAbs. We tested the T-cell costimulatory function of these molecules in vitro using primary human T cells and human cancer cell lines. Based on these results, we selected a clinical candidate which we assessed in a syngeneic mouse tumor model system and investigated tolerability and pharmacokinetics (PK) in non-human primates (NHP). Results Our in vitro studies demonstrated that these bsAbs effectively enhance T-cell activation and cytotoxicity against Nectin-4 positive tumor cells in the presence of T-cell receptor engagement. The bsAb panel exhibited a range of potencies, enabling the selection of a clinical candidate, termed RNDO-564, that maximized antitumor efficacy as well as the likelihood of a broad therapeutic window. Tumor-bearing syngeneic mouse models confirmed the in vivo efficacy of RNDO-564, demonstrating significant tumor regression both as a single agent and in combination with an immune checkpoint inhibitor. We observed favorable PK and tolerability profiles in NHP assessments. Conclusions Our study reports the first CD28 bsAb targeting Nectin-4 and highlights the potential of CD28 × Nectin-4 bsAbs as a new immunotherapeutic modality. The findings support the clinical development of RNDO-564 in patients with locally advanced and metastatic UC and other Nectin-4 positive malignancies.
Authors: Manpreet Kaur, Katja Rüger, Elaine C Chen, Udaya S Rangaswamy, Laura M Davison, Sebastian Moreno Arteaga, Imani Smith, Ruth Chu, Soumili Chattopadhyay, Mathias Rickert, Shelley Force Aldred, Katherine E Harris, Nathan D Trinklein, Starlynn C Clarke
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W4409184547