AGB101, a first-in-class Vβ17 x DLL3 bispecific antibody, selectively redirects Vβ17 T memory cells to drive robust DLL3 dependent anti-tumor activity
Presenter: Matthew Lorenzi, PhD Session: Late-Breaking Research: Immunology 3 Time: 4/21/2026 9:00:00 AM → 4/21/2026 12:00:00 PM
Authors
Natasa Obermajer , Jessie Richardson , Daniel Masylar , Karin Thacker , Matthew V. Lorenzi , Iqbal S. Grewal Agni Bio, Palo Alto, CA
Abstract
CD3-based bispecific antibodies (bsAbs) that recruit pan-T cells to target tumor-associated antigens (TAAs) have shown clinical benefit but their use is limited by high rates of immune-related toxicities such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), arising from broad T cell activation following CD3 engagement. In addition, CD3 bsAbs recruit antagonizing T cell subpopulations such as regulatory or exhausted T cells that can narrow the therapeutic index and affect durability of response. To overcome these limitations, we developed a novel bsAb platform (anti-TRBV19 x anti-TAA) that selectively activates the TRBV19 (Vβ17) chain of the T cell receptor. The Vβ17 T cell subset is a memory population that constitutes 5% of circulating T cells in healthy individuals and cancer patients. Vβ17 T cells exhibit cytotoxic activity, enhanced persistence, and reduced susceptibility to exhaustion. Their selective recruitment enables more efficient anti-tumor immune responses, sparing activation of non-effector T cells. AGB101, is a highly optimized Vβ17 bsAb targeting the solid tumor lineage antigen DLL3 that is overexpressed in small cell lung cancer (SCLC) and other neuroendocrine tumor types. AGB101 demonstrates DLL3-dependent activation and selective expansion of Vβ17 T cells while the broader population of T cells, including naïve T cells, remain unaffected. In contrast, treatment with the CD3 x DLL3 bsAb, tarlatamab, leads to a rapid expansion of the entire T cell population including non-cytolytic subsets. In human PBMC/SHP-77 (DLL3+) co-culture assays, AGB101 showed equivalent cytotoxicity to tarlatamab, despite engaging 15-20-fold fewer immune effector cells, indicating that effector cell type rather than their prevalence mediates anti-tumor cytotoxic responses. AGB101 selectively and robustly expanded CD8+ Vβ17 T cells with minimal CD4+ T cell expansion and induced stronger effector cell activation compared to CD3 engagement. In addition, AGB101 significantly increased the expansion of CCR7+/CD45RO+ memory T cells compared to tarlatamab treatment. Notably, AGB101 treatment resulted in much lower levels of cytokine release, particularly pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β), compared to tarlatamab treatment. Lastly, AGB101 demonstrated robust anti-tumor activity in vivo in two DLL3 expressing SCLC tumor models. Collectively, our data demonstrate that TCR-directed targeting improves the quality, magnitude, and durability of anti-tumor T cell responses and these features of AGB101 mediated anti-tumor activity highlight selective Vβ17 T cell redirection as a promising next-generation immunotherapeutic approach to enable more efficient immune system engagement, with the potential to provide improved clinical benefit to patients.
Disclosure
N. Obermajer, Agni Bio Employment, Stock Option, Patent. J. Richardson, Agni Bio Employment, Stock Option, Patent. D. Masylar, Agni Bio Employment, Stock Option. K. Thacker, Agni Bio Employment, Stock Option. M. V. Lorenzi, Agni Bio Employment, g., Board of Directors, non-salaried role), Stock Option, Patent. I. S. Grewal, Agni Bio Employment, Stock Option, Patent.
Cited in
Control: 10338 · Presentation Id: 11548 · Meeting 21436