A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer.

Autor:	Avanzino BC; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA., Prabhakar K; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA., Dalvi P; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA., Hartstein S; Teneobio, Inc, Newark, CA, United States.; Therapeutic Discovery, Amgen Inc., Newark, CA, USA., Kehm H; Teneobio, Inc, Newark, CA, United States., Balasubramani A; Teneobio, Inc, Newark, CA, United States.; Therapeutic Discovery, Amgen Inc., Newark, CA, USA., Boudreau AA; Teneobio, Inc, Newark, CA, United States., Buelow B; Teneobio, Inc, Newark, CA, United States., Chang K; Teneobio, Inc, Newark, CA, United States., Davison LM; Teneobio, Inc, Newark, CA, United States., Iyer S; Teneobio, Inc, Newark, CA, United States., Kalwit V; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA., Lewis Wilson K; Translational Safety & Bioanalytical Sciences, Amgen Inc., South San Francisco, CA, USA., Malik-Chaudhry HK; Teneobio, Inc, Newark, CA, United States.; Therapeutic Discovery, Amgen Inc., Newark, CA, USA., Pierson W; Division of Gynecologic Oncology, University of California, San Francisco, CA, USA.; University of Rochester School of Medicine and Dentistry, Rochester, NY, USA., Pineda G; Division of Gynecologic Oncology, University of California, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Rangaswamy US; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA., Saiganesh S; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA., Schellenberger U; Teneobio, Inc, Newark, CA, United States., Ugamraj HS; Teneobio, Inc, Newark, CA, United States.; Process Development, Amgen Inc., Newark, CA, USA., Yabut RD; Translational Safety & Bioanalytical Sciences, Amgen Inc., South San Francisco, CA, USA., Buelow R; Teneobio, Inc, Newark, CA, United States., Chapman J; Division of Gynecologic Oncology, University of California, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Trinklein ND; Teneobio, Inc, Newark, CA, United States., Harris KE; Teneobio, Inc, Newark, CA, United States.; Oncology Research, Amgen Inc., Newark, CA, USA.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2022 Aug 20; Vol. 11 (1), pp. 2113697. Date of Electronic Publication: 2022 Aug 20 (Print Publication: 2022).
DOI:	10.1080/2162402X.2022.2113697
Abstrakt:	The use of T-cell engagers (TCEs) to treat solid tumors is challenging, and several have been limited by narrow therapeutic windows due to substantial on-target, off-tumor toxicities due to the expression of low levels of target antigens on healthy tissues. Here, we describe TNB-928B, a fully human TCE that has a bivalent binding arm for folate receptor alpha (FRα) to selectively target FRα overexpressing tumor cells while avoiding the lysis of cells with low levels of FRα expression. The bivalent design of the FRα binding arm confers tumor selectivity due to low-affinity but high-avidity binding to high FRα antigen density cells. TNB-928B induces preferential effector T-cell activation, proliferation, and selective cytotoxic activity on high FRα expressing cells while sparing low FRα expressing cells. In addition, TNB-928B induces minimal cytokine release compared to a positive control TCE containing OKT3. Moreover, TNB-928B exhibits substantial ex vivo tumor cell lysis using endogenous T-cells and robust tumor clearance in vivo , promoting T-cell infiltration and antitumor activity in mouse models of ovarian cancer. TNB-928B exhibits pharmacokinetics similar to conventional antibodies, which are projected to enable favorable administration in humans. TNB-928B is a novel TCE with enhanced safety and specificity for the treatment of ovarian cancer. Competing Interests: All authors except K.L.W., W.P., G.P., R.D.Y., and J.C. are current or former employees of Teneobio, Inc. with equity interests when the study was conducted and reported. B.C.A., K.P., P.D., S.H., A.B., A.A.B., L.M.D., V.K., K.L.W., H.K.M.C., U.S.R., S.S., H.S.U., R.D.Y., and K.E.H. are current or former employees of Amgen, Inc. (© 2022 Amgen, Inc. Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu