Abstract Nectin-4 is a tumor-associated antigen (TAA) that is commonly overexpressed on numerous solid tumor types, including urothelial, head and neck, and triple-negative breast cancer. Nectin-4 is also expressed at low levels on normal, healthy tissues, which limits current ADC therapies due to high rates of dose-limiting, on-target, off-tumor toxicities. Furthermore, patients previously benefiting from ADC therapy become resistant to treatment. This highlights a need for alternative approaches for anti-cancer therapeutics that can selectively target Nectin-4 expressing solid tumors with an improved mechanism of action. A highly selective and potent trivalent VHH based Nectin-4 x CD3 T-cell engager (TCE) was generated using LabGenius Therapeutics’ proprietary discovery engine (EVA™). By harnessing avidity-driven selectivity, LabGenius’ Nectin-4 x CD3 TCE (LGTX-101) is able to differentiate between healthy and diseased cells based on differential TAA expression. LALA mutations were introduced to abrogate FcyR activity. The potency and selectivity of the lead molecule LGTX-101 was tested in a range of tumor cell line cytotoxicity models with varying expression of Nectin-4, including primary bladder cancer cells. Furthermore, the in vivo efficacy was established using a humanised BT-474 CDX model. LGTX-101 has a 3:1 Nectin-4:CD3 stoichiometry capable of high affinity binding to Nectin-4 expressing cells and low-moderate affinity to human CD3. In in vitro tumor cell cytotoxicity assays, LGTX-101 potently induced cytotoxicity in cancer cell lines with Nectin-4 receptor expression levels within 2-fold of healthy control model cell lines, with mean EC50 potency of 0.712 +/- 0.132 pM. No evidence of cytotoxicity of the healthy cell model was observed, demonstrating a 1,000-fold therapeutic window between Nectin-4 positive normal and tumor cell cytotoxicity. These observations were further extended to primary bladder cancer co-cultures, where LGTX-101 induced activation of T cells at concentrations of 5 pM. Furthermore, no evidence of T cell activation was observed when PBMCs were cultured with human primary keratinocytes, known to express low levels of Nectin-4. Finally, LGTX-101 demonstrated robust reduction of the growth of established tumors in vivo in a humanized BT-474 xenograft model (90% tumor growth inhibition) and a preliminary PK profile that supports a Q2W - Q4W dosing regimen in the clinic. LGTX-101 is a highly selective and highly efficacious Nectin-4 x CD3 TCE currently in preclinical development for treatment of advanced solid tumors. With an increased selectivity and potency profile, LGTX-101 has the potential to provide a safer, more effective treatment option for patients. Citation Format: Lucrecia Alberdi, Sabrina Bouhafs, Dan Foxler, Justin Grace, Winston Haynes, Catherine Howsham, Leo Kassimatis, Sylwia Marshall, Lida Mavrogonatou, James McClory, Portia McGhan, Rebecca Mighell, Michael Mullin, Sandra Pasternakiewicz, Sujata Ravi, Nush Sarvaria, Gino Van Heeke, Angus Sinclair, . A novel machine-learning derived nectin-4 x CD3 bispecific T-cell engager, LGTX-101, demonstrates high degrees of tumor selectivity and potently induces tumor regression in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1626.
Alberdi et al. (Fri,) studied this question.