AbstractBackground:Abnormal EGFR signaling, increased cMET activation, and VEGF-induced angiogenesis are responsible for the growth and metastasis of many difficult to treat solid tumors. TAVO412 is a humanized multi-specific antibody with two distinct anti-EGFR nanobody-like domains, an anti-cMET Fab arm, and an anti-VEGF ScFv domain. In addition, the Fc domain allows for the heterodimerization, antibody-like pharmacokinetic profile, and additional mutations that enhance the Fc effector functions. TAVO412 had strong in vivo tumor growth inhibition in the preclinical models of NSCLC, gastrointestinal and esophageal cancers, PDAC, TNBC, and other solid tumor models. TAVO412 also had strong tumor growth inhibition as demonstrated against NSCLC patient derived xenograft (PDX) models with various mutant EGFR and cMet genotypes. Stronger activities were also demonstrated when TAVO412 was in combination with docetaxel, TKIs, and with radiotherapy.Methods:The clinical study (TAVOTEK412-CN001) is a two-part, open-label, non-randomized, Phase I study to determine the safety and tolerability, to define the MTD/RP2D, and to assess the preliminary efficacy of TAVO412 in patients with advanced or metastatic solid tumors who progressed on prior standard-of-care therapies (Clinical trial NCT06761651). Part 1 of the study is a dose escalation by a standard 3+3 design, mainly for safety and tolerability with 5 dose cohorts up to 1500 mg. Part 2 of the study is an extension of the study in about 100 patients based on the preliminary information obtained in Part 1 regarding dose levels, type of tumor showing preliminary efficacy signals, and genetic makeup. At the time of this abstract, 25 patients with a variety of solid tumors have been enrolled in Part 1 dose escalation. Since no DLT have been observed and MTD has not been reached, an additional dose level at 1750 mg will be tested. Meanwhile, the safety and efficacy signals are being enhanced by the backfill of patients to the safe and potential efficacious dose cohorts starting Q1 2025. The Part 2 of the study is expected to start in Q4 2025. Keywords: trispecific antibody, EGFR, cMET, VEGF, gastrointestinal cancers, lung cancersEthics approval: “This study was approved by CRADL-Suzhou’s Ethics Board; approval number P202302160002.NMPA IND Approval number 2023LP01660; Henan Cancer Hospital Ethics Board approval number 2023-314-003Citation Format:Mark Chiu, Wei Zhang, Yanjiao Yu, Helen Jiang, Chao Han. Trispecific EGFR x cMET x VEGF antibody, TAVO412, has clinical responses in esophageal and lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT185.

2025-04-21·Cancer Research

Abstract 2880: TM4SF1 as a novel target for different modalities (mAb, bispecific ADC, targeted siRNA) for the treatment of different solid tumor cancers

作者: Lu, Han ; Pandey, Poonam ; Motohiko, Nishida ; Chiu, Mark ; MacWilliams, Maria P. ; Wilski, Nicole ; Dong, ShuTing ; Li, Peter ; Haytko, Peter ; Xie, Mingquan

Background:Transmembrane-4-L-six-family member-1 (TM4SF1) is a tetraspanin superfamily member that is overexpressed in cancers such as breast, colon, lung, liver, and prostate. A contributor to tumor development and progression, TM4SF1 participates in microdomains that regulate cancer cell migration and invasion via induction of the epithelial-mesenchymal transition, and angiogenesis. The overexpression of TM4SF1 makes it an attractive target for the developing novel treatments of GI tract cancers.Methods and Results:We have engineered an anti-TM4SF1 antibody that binds with nM affinity to TM4SF1-expressing cells. The mAb has anti-tumor growth inhibition in gastric, ovarian cancer cell lines. This mAb can serve as an efficacious targeting carrier for toxins in an ADC and for siRNA in an ARC. To broaden the scope of cancer cell engagement, we prepared constructed a TM4SF1-cMET bispecific ADC which showed potent cytotoxicity in multiple GI, lung, ovarian, breast, TNBC, and pancreatic cancer cell lines in in vitro cell cytotoxicity assays. The bispecific TM4SF1-cMET MMAE (DAR=4) treatment led to potent tumor growth inhibition (70% to 95% TGI) in CDX pancreatic and gastric cancer xenograft models. The mice in the TM4SF1-cMET MMAE treatment group maintained normal body weight throughout the treatment course without observed toxicity. The TM4SF1 - MYC siRNA conjugates were stable. Treatment of MYC-dependent cancer lines led to MYC protein knockdown and cell growth inhibition.Conclusions:A bispecific TM4SF1 ADC had activity in multiple cancer cell lines. Notably, the TM4SF1-MMAE molecule showed potent in vivo tumor growth inhibition in ovarian, pancreatic, and gastric cell lines. The TM4SF1 - siRNA ARC had tumor cell proliferation inhibition in lung, pancreatic, and gastric cancer cell lines. Preclinical safety assessment, pharmacokinetics and IND-enabling studies are on-going with the goal of developing TM4SF1 as the “best-in-class” ADC molecule for the treatment of lung, gastric, breast, and pancreatic cancers with significant unmet medical needs. This antibody can be applied to alternative targeting modalities.Citation Format:Mingquan Xie, Peter Li, Han Lu, ShuTing Dong, Nicole Wilski, Poonam Pandey, Nishida Motohiko, Peter Haytko, Mark Chiu, Maria P. MacWilliams. TM4SF1 as a novel target for different modalities (mAb, bispecific ADC, targeted siRNA) for the treatment of different solid tumor cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2880.

2023-04-04·Cancer Research

Abstract 4494: Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers

作者: Chiu, Mark

AbstractCancers such as TNBC, pancreatic, and gastric are difficult to treat due to diverse etiologies. Several subtypes of these cancers are driven by abnormal EGFR signaling, increased cMET activation, and VEGF linked angiogenesis which are responsible for tumor growth and metastasis. TAVO412, a humanized multi-specific antibody with two distinct anti-EGFR nanobody domains, an anti-cMet Fab arm, and an anti-VEGF ScFv domain, was designed to treat patients with these unmet medical needs. In addition, the Fc domain allows for the heterodimerization, antibody-like pharmacokinetic profile, and additional mutations that enhance the Fc effector functional activity. In preclinical xenograft models, TAVO412 demonstrated strong tumor growth inhibition effects on TNBC, PDAC, GC or NSCLC cell line-derived tumors. The mechanisms of action included selective and potent binding to EGFR, cMet, and VEGF at lower pH values found in the solid tumor environment; effective blocking of EGFR and cMet pathways that drove cancer cell growth and proliferation; shutdown of VEGF mediated angiogenesis; and potent and efficacious Fc effector function that enhanced ADCC, ADCP, and CDC. TAVO412 had better TGI than analogous molecules. TAVO412 also demonstrated strong tumor growth inhibition against NSCLC patient derived xenograft (PDX) models with mutant EGFR and cMet genotypes. Each of the binding arms had cross reactivity with the cynomolgus monkey orthologues allowing the cyno model to be a relevant toxicology model. In the pivotal GLP toxicology study in cynomolgus monkeys, TAVO412 was well tolerated, had no major organ toxicities, observations were mostly consistent with EGFR-related effects and recoverable. In conclusion, TAVO412 was successfully discovered and developed for hard-to-treat solid tumors. This drug is expected to be safe and efficacious in cancer patients. The IND application was approved by the US FDA in October 2022. A first-in-human, 2-Part Phase 1 study to examine the preliminary efficacy, safety, tolerability, pharmacokinetic/pharmacodynamic parameters; maximum tolerated dose/recommended phase 2 dose of TAVO412 will be starting in the first quarter of 2023.Citation Format: Mark Chiu. Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4494.

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