Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer-Reference-Cited by-同舟云学术

Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer

Published:2024-04-02 Issue:6 Volume:12 Page:719-730
ISSN:2326-6066
Container-title:Cancer Immunology Research
language:en
Short-container-title:

Author:

Mikami Hirofumi¹^ORCID,Feng Shu²^ORCID,Matsuda Yutaka³^ORCID,Ishii Shinya¹^ORCID,Naoi Sotaro²^ORCID,Azuma Yumiko¹^ORCID,Nagano Hiroaki²^ORCID,Asanuma Kentaro¹^ORCID,Kayukawa Yoko¹^ORCID,Tsunenari Toshiaki¹^ORCID,Kamikawaji Shogo¹^ORCID,Iwabuchi Ryutaro¹^ORCID,Shinozuka Junko¹^ORCID,Yamazaki Masaki¹^ORCID,Kuroi Haruka¹^ORCID,Ho Samantha Shu Wen²^ORCID,Gan Siok Wan²^ORCID,Chichili Priyanka²^ORCID,Pang Chai Ling²^ORCID,Yeo Chiew Ying²^ORCID,Shimizu Shun¹^ORCID,Hironiwa Naoka²^ORCID,Kinoshita Yasuko¹^ORCID,Shimizu Yuichiro¹^ORCID,Sakamoto Akihisa¹^ORCID,Muraoka Masaru¹^ORCID,Takahashi Noriyuki²^ORCID,Kawa Tatsuya¹^ORCID,Shiraiwa Hirotake¹^ORCID,Mimoto Futa²^ORCID,Kashima Kenji¹^ORCID,Kamata-Sakurai Mika¹^ORCID,Ishikawa Shumpei⁴^ORCID,Aburatani Hiroyuki⁵^ORCID,Kitazawa Takehisa¹^ORCID,Igawa Tomoyuki⁶^ORCID

Affiliation:

1. 1Research Division, Chugai Pharmaceutical, Yokohama, Kanagawa, Japan.

2. 2Research Division, Chugai Pharmabody Research, Singapore, Singapore.

3. 3Project & Lifecycle Management Unit, Chugai Pharmaceutical, Chuo-ku, Tokyo, Japan.

4. 4Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.

5. 5Genome Science Division, Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Meguro-ku, Tokyo, Japan.

6. 6Translational Research Division, Chugai Pharmaceutical, Chuo-ku, Tokyo, Japan.

Abstract

Abstract Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

Funder

n/a

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/cancerimmunolres/article-pdf/doi/10.1158/2326-6066.CIR-23-0638/3431422/cir-23-0638.pdf

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