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- 조회122
원종화Jonghwa Won
에이비엘바이오
J. Immunother. Cancer, Feb 25 2025, 13 (2) e010728 | https://doi.org/10.1136/jitc-2024-010728
Fc-competent TIGITx4-1BB bispecific antibody exerts potent long-lasting antitumor activity by potentiating CD8+ T cell activity and Fcγ receptor-mediated modulation of the tumor microenvironment
Wonjun Son,1 Yangsoon Lee,1 Yelim Park,1 Kyeong-Su Park,1 Sora Kim,1 Hyunseong Youn,1 Arim Seo,2 Byungje Sung,3 Sang Hoon Lee,4 Jonghwa Won 1
1Oncology Discovery, ABL Bio Inc, Seongnam, Korea (the Republic of)
2Quality Control, ABL Bio Inc, Seongnam, Korea (the Republic of)
3Analytics, ABL Bio Inc, Seongnam, Korea (the Republic of)
4ABL Bio Inc, Seongnam, Korea (the Republic of)
Correspondence to Dr Jonghwa Won
1Oncology Discovery, ABL Bio Inc, Seongnam, Korea (the Republic of)
2Quality Control, ABL Bio Inc, Seongnam, Korea (the Republic of)
3Analytics, ABL Bio Inc, Seongnam, Korea (the Republic of)
4ABL Bio Inc, Seongnam, Korea (the Republic of)
Correspondence to Dr Jonghwa Won
Abstract
Background: TIGIT was identified as a target immune checkpoint for overcoming resistance to PD-(L)1-blocking antibodies. However, the clinical efficacies of TIGIT antibodies were moderate in monotherapy and mixed in combination with PD-(L)1 antibodies. 4-1BB, a strong inducible costimulatory receptor, is another attractive target in antitumor therapeutics. This study investigated whether ABL112, an Fc-competent bispecific antibody targeting TIGIT and 4-1BB (TIGITx4-1BB), would enhance antitumor activity via Fcγ receptor (FcγR)-mediated macrophage activation and antibody-dependent cell-mediated functions.
Methods: TIGIT-dependent 4-1BB activation and TIGIT-blocking activity were assessed using reporter Jurkat T cell lines expressing 4-1BB and TIGIT, respectively. In vivo antitumor activity was confirmed in h4-1BB knock-in mice. The main immune cell subsets associated with the antitumor activity of ABL112 were identified using antibodies for depleting specific immune cell subtypes or FcγR-blocking antibodies. The effects of a combined pembrolizumab or atezolizumab treatment with ABL112 were assessed in two mouse models with different genetic backgrounds. Statistical analysis was performed using one-way or two-way analysis of variance (ANOVA) with Dunnett's multiple-comparison test or one-way ANOVA with Fisher's multiple-comparison test.
Results: ABL112 restored T cell activity by blocking TIGIT-CD155 interactions, based on a TIGIT blockade reporter assay. ABL112, an Fc-competent TIGITx4-1BB bispecific antibody, showed strong FcγRI-dependent 4-1BB activation along with TIGIT-dependent 4-1BB activation. In H22 tumor models expressing high levels of endogenous CD155, both ABL112 and parent TIGIT single-domain Ab showed potent tumor-suppressive activity; however, only ABL112 exerted long-lasting antitumor activity. ABL112 induced a marked decrease in Treg numbers, while augmenting the absolute number of CD8+ T cells and proportion of CD226+ CD8+ T cells. The expressions of CXCL10, CXCL11, IFN-γ, and TNF-α increased, indicating myeloid cell activation and potential modification of the tumor microenvironment to an inflammatory phenotype. ABL112 not only showed outstanding antitumor activity as a monotherapy, but also showed synergistic effects with PD-(L)1 mAb compared with the combined TIGIT-PD-(L)1 mAb treatments.
Conclusions: Through multiple mechanisms of action, ABL112 exerted potent tumor-killing activity and immune memory response alone or in combination with anti-PD-(L)1 therapies, representing a promising new cancer treatment strategy.
Methods: TIGIT-dependent 4-1BB activation and TIGIT-blocking activity were assessed using reporter Jurkat T cell lines expressing 4-1BB and TIGIT, respectively. In vivo antitumor activity was confirmed in h4-1BB knock-in mice. The main immune cell subsets associated with the antitumor activity of ABL112 were identified using antibodies for depleting specific immune cell subtypes or FcγR-blocking antibodies. The effects of a combined pembrolizumab or atezolizumab treatment with ABL112 were assessed in two mouse models with different genetic backgrounds. Statistical analysis was performed using one-way or two-way analysis of variance (ANOVA) with Dunnett's multiple-comparison test or one-way ANOVA with Fisher's multiple-comparison test.
Results: ABL112 restored T cell activity by blocking TIGIT-CD155 interactions, based on a TIGIT blockade reporter assay. ABL112, an Fc-competent TIGITx4-1BB bispecific antibody, showed strong FcγRI-dependent 4-1BB activation along with TIGIT-dependent 4-1BB activation. In H22 tumor models expressing high levels of endogenous CD155, both ABL112 and parent TIGIT single-domain Ab showed potent tumor-suppressive activity; however, only ABL112 exerted long-lasting antitumor activity. ABL112 induced a marked decrease in Treg numbers, while augmenting the absolute number of CD8+ T cells and proportion of CD226+ CD8+ T cells. The expressions of CXCL10, CXCL11, IFN-γ, and TNF-α increased, indicating myeloid cell activation and potential modification of the tumor microenvironment to an inflammatory phenotype. ABL112 not only showed outstanding antitumor activity as a monotherapy, but also showed synergistic effects with PD-(L)1 mAb compared with the combined TIGIT-PD-(L)1 mAb treatments.
Conclusions: Through multiple mechanisms of action, ABL112 exerted potent tumor-killing activity and immune memory response alone or in combination with anti-PD-(L)1 therapies, representing a promising new cancer treatment strategy.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-28)
- 국내 연구진
- 의약학 > 면역의학
관련 보도자료
에이비엘바이오, 국제 저명 학술지 JITC에 'ABL112' 연구 결과 게재
이중항체 전문기업 에이비엘바이오(대표 이상훈)는 이중항체 면역항암제 ABL112에 대한 논문을 미국면역항암학회(Society for Immunotherapy of Cancer, SITC)가 발행하는 국제 학술지 JITC(Journal for ImmunoTherapy of Cancer)를 통해 발표했다고 4일 밝혔다. JITC는 영향력 지수(Impact Factor) 10.3의 권위 있는 국제 학술지로, 종양 면역학 및 면역치료와 관련된 다양한 논문을 게재한다.
- 약업신문
- 2025. 03. 04
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