Phase 1, first-in-human, open-label study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of TGW101 in patients with advanced solid tumors.

TPS3163 Background: Tumor-associated glycoprotein 72 (TAG-72) is a non-internalizing glycoepitope that is aberrantly expressed in a broad range of epithelial cancers, predominantly adenocarcinomas. TGW101 is an antibody-drug conjugate (ADC) therapy that utilizes a novel, bio-orthogonal click chemistry-based linker technology that enables the targeting of non-internalizing cancer antigens and controlled payload release. The first component of TGW101 is a chemically cleavable ADC (TGW101-ADC) that consists of a diabody targeting TAG-72 and a highly stable trans -cyclooctene (TCO) linker conjugated to a monomethyl auristatin E (MMAE) payload. Once the TGW101-ADC binds to intratumoral TAG-72 and is largely cleared from the systemic circulation, the second drug component, a tetrazine trigger (TRG001), is administered, leading to rapid MMAE release from TGW101-ADC via a selective cleavage reaction with the TCO linker. Upon release of MMAE into the tumor microenvironment, it readily diffuses into surrounding tumor cells, binds to microtubules, inhibits cell cycle progression, and activates local immune cells. In preclinical studies, TGW101 treatment led to tumor regressions in the OVCAR3 (ovarian) cell line and GXF214 (gastric) patient-derived xenograft model, and improved survival in LS174T (colon) tumor bearing mice. Methods: This first-in-human, open-label Phase 1 study evaluates the safety and tolerability of TGW101 and defines a maximum tolerated dose (MTD). A Bayesian Optimal Interval (BOIN) design is used to determine the recommended dosing regimen(s) for expansion. Secondary objectives include assessing the pharmacokinetic (PK) profile, intratumoral pharmacodynamics, preliminary anti-tumor activity, and immunogenicity of TGW101. Exploratory analysis will investigate the relationship between TAG-72 expression and tumor response, as well as the effect of TGW101 exposure on tumor biomarkers. Up to 50 participants with advanced solid tumors, including breast, NSCLC, prostate, cervical, endometrial, ovarian, gastroesophageal, and non-squamous cell carcinoma of the head and neck are planned for enrollment. During dose escalation, increasing doses of TGW101-ADC, administered intravenously on Day 1 followed 7 days later by a fixed-dose infusion of TRG001, will be explored in cohorts of 3-4 participants treated in 3-week cycles. Once pharmacologically active dose levels are identified, specific cohorts may enroll additional participants to further explore safety, PK, tumor biomarker changes, and efficacy. Adverse events are assessed according to CTCAE v5 and tumor response is determined by RECIST 1.1 or PCWG3 criteria every 6 weeks for the first 2 cycles, then every 9 weeks. The trial began in May 2025 and 7 sites, all within the United States, are open for enrollment. Clinical trial information: NCT06959706 .