A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer
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...
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2113697 |
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| author | Brian C. Avanzino Kirthana Prabhakar Pranjali Dalvi Sharon Hartstein Hannes Kehm Aarti Balasubramani Andrew A. Boudreau Ben Buelow Karen Chang Laura M. Davison Suhasini Iyer Vidyut Kalwit Kristin Lewis Wilson Harbani K. Malik-Chaudhry Will Pierson Geovanni Pineda Udaya S. Rangaswamy Sowmya Saiganesh Ute Schellenberger Harshad S. Ugamraj Rodolfovan D. Yabut Roland Buelow Jocelyn Chapman Nathan D. Trinklein Katherine E. Harris |
| author_facet | Brian C. Avanzino Kirthana Prabhakar Pranjali Dalvi Sharon Hartstein Hannes Kehm Aarti Balasubramani Andrew A. Boudreau Ben Buelow Karen Chang Laura M. Davison Suhasini Iyer Vidyut Kalwit Kristin Lewis Wilson Harbani K. Malik-Chaudhry Will Pierson Geovanni Pineda Udaya S. Rangaswamy Sowmya Saiganesh Ute Schellenberger Harshad S. Ugamraj Rodolfovan D. Yabut Roland Buelow Jocelyn Chapman Nathan D. Trinklein Katherine E. Harris |
| author_sort | Brian C. Avanzino |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9e96f15bb0a54d7bb137adf3be604c3c |
| institution | DOAJ |
| issn | 2162-402X |
| language | English |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-9e96f15bb0a54d7bb137adf3be604c3c2025-08-20T03:01:51ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2113697A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancerBrian C. Avanzino0Kirthana Prabhakar1Pranjali Dalvi2Sharon Hartstein3Hannes Kehm4Aarti Balasubramani5Andrew A. Boudreau6Ben Buelow7Karen Chang8Laura M. Davison9Suhasini Iyer10Vidyut Kalwit11Kristin Lewis Wilson12Harbani K. Malik-Chaudhry13Will Pierson14Geovanni Pineda15Udaya S. Rangaswamy16Sowmya Saiganesh17Ute Schellenberger18Harshad S. Ugamraj19Rodolfovan D. Yabut20Roland Buelow21Jocelyn Chapman22Nathan D. Trinklein23Katherine E. Harris24Teneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTranslational Safety & Bioanalytical Sciences, Amgen Inc., South San Francisco, CA, USATeneobio, Inc, Newark, CA, United StatesDivision of Gynecologic Oncology, University of California, San Francisco, CA, USADivision of Gynecologic Oncology, University of California, San Francisco, CA, USATeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesTranslational Safety & Bioanalytical Sciences, Amgen Inc., South San Francisco, CA, USATeneobio, Inc, Newark, CA, United StatesDivision of Gynecologic Oncology, University of California, San Francisco, CA, USATeneobio, Inc, Newark, CA, United StatesTeneobio, Inc, Newark, CA, United StatesThe 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.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2113697Bispecific antibodyT-cell engagerfolate receptor alphaovarian canceron-target, off-tumor toxicity |
| spellingShingle | Brian C. Avanzino Kirthana Prabhakar Pranjali Dalvi Sharon Hartstein Hannes Kehm Aarti Balasubramani Andrew A. Boudreau Ben Buelow Karen Chang Laura M. Davison Suhasini Iyer Vidyut Kalwit Kristin Lewis Wilson Harbani K. Malik-Chaudhry Will Pierson Geovanni Pineda Udaya S. Rangaswamy Sowmya Saiganesh Ute Schellenberger Harshad S. Ugamraj Rodolfovan D. Yabut Roland Buelow Jocelyn Chapman Nathan D. Trinklein Katherine E. Harris A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer OncoImmunology Bispecific antibody T-cell engager folate receptor alpha ovarian cancer on-target, off-tumor toxicity |
| title | A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer |
| title_full | A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer |
| title_fullStr | A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer |
| title_full_unstemmed | A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer |
| title_short | A T-cell engaging bispecific antibody with a tumor-selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer |
| title_sort | t cell engaging bispecific antibody with a tumor selective bivalent folate receptor alpha binding arm for the treatment of ovarian cancer |
| topic | Bispecific antibody T-cell engager folate receptor alpha ovarian cancer on-target, off-tumor toxicity |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2113697 |
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