一种新型机器学习衍生的nectin-4 x CD3双特异性T细胞衔接器LGTX-101表现出高度的肿瘤选择性并在体内强效诱导肿瘤消退

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 EC 50 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.