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© 2022 Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Background

Despite clinical success with T cell engagers (TCEs) targeting hematological malignancies, achieving a safe and efficacious dose in patients with solid tumors remains challenging. Due to potency, low levels of target antigen expression on normal tissues may not be tolerated. To overcome this, we engineered a novel conditionally active TCE design called COBRA (Conditional Bispecific Redirected Activation). Administered as prodrugs, COBRAs bind to cell surface antigens on both normal and tumor tissues but are preferentially activated within the tumor microenvironment.

Methods

A COBRA was engineered to target EGFR, TAK-186. The potency of precleaved TAK-186 relative to a non-cleavable control was assessed in vitro. Mice bearing established solid tumors expressing a range of EGFR levels were administered a single bolus of human T cells, and concurrently treated with TAK-186 and associated controls intravenously. We assessed the plasma and tumor exposure of intact and cleaved TAK-186.

Results

TAK-186 shows potent redirected T cell killing of antigen expressing tumor cells. In vivo efficacy studies demonstrate regressions of established solid tumors, dependent on intratumoral COBRA cleavage. Pharmacokinetic studies reveal TAK-186 is stable in circulation, but once activated is rapidly cleared due to loss of its albumin-binding half-life extension domain.

Conclusions

The studies shown support the advancement of TAK-186, and the pursuit of additional COBRA TCEs for the treatment of solid tumors.

Details

Title
Regression of EGFR positive established solid tumors in mice with the conditionally active T cell engager TAK-186
Author
Dettling, Danielle E 1   VIAFID ORCID Logo  ; Kwok, Eilene 1 ; Quach, Lucy 1 ; Datt, Aakash 1 ; Degenhardt, Jeremiah D 1 ; Panchal, Anand 1 ; Seto, Pui 1 ; Krakow, Jessica L 1 ; Wall, Russell 1 ; Hillier, Brian J 1 ; Zhu, Ying 1 ; Vinogradova, Maia 1 ; DuBridge, Robert B 1 ; May, Chad 1 

 Oncology Drug Development Unit, Takeda Development Centers America, Inc (TDCA), Lexington, Massachusetts, USA 
First page
e004336
Section
Clinical/translational cancer immunotherapy
Publication year
2022
Publication date
Jun 2022
Publisher
BMJ Publishing Group LTD
e-ISSN
20511426
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2679365867
Copyright
© 2022 Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ . Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.