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원종화Jonghwa Won

에이비엘바이오

J. Immunother. Cancer, Oct 2023, 11 (10) e007494 | https://doi.org/10.1136/jitc-2023-007494 Asymmetric anti-CLL-1×CD3 bispecific antibody, ABL602 2+1, with attenuated CD3 affinity endows potent antitumor activity but limited cytokine release

Eunhee Lee,¹ Shinai Lee,¹ Sumyeong Park,¹ Yong- Gyu Son,¹ Jiseon Yoo,¹ Youngil Koh,² Dong- Yeop Shin,² Yangmi Lim,¹ Jonghwa Won¹

¹ABL Bio Inc, Seongnam, Korea (the Republic of)

²Department of Internal Medicine, Seoul National University Hospital, Jongno- gu, Korea (the Republic of)

Correspondence to Dr Jonghwa Won; Dr Yangmi Lim

Abstract

Acute myeloid leukemia (AML) is a type of leukemia in adults with a high mortality rate and poor prognosis. Although targeted therapeutics, chemotherapy, and hematopoietic stem cell transplantation can improve the prognosis, the recurrence rate is still high, with a 5-year survival rate of approximately 40%. This study aimed to develop an IgG-based asymmetric bispecific antibody that targets CLL-1 and CD3 for treating AML. ABL602 candidates were compared in terms of binding activity, T-cell activation, and tumor-killing activities. ABL602-mediated T-cell activation and tumor-killing activities were determined by measuring the expression of activation markers, cytokines, cytolytic proteins, and the proportion of dead cells. We evaluated in vivo tumor growth inhibitory activity in two mouse models bearing subcutaneously and orthotopically engrafted human AML. Direct tumor-killing activity and T-cell activation in patient-derived AML blasts were also evaluated. ABL602 2+1 showed a limited CD3 binding in the absence of CLL-1, suggesting that steric hindrance on the CD3 binding arm could reduce CLL-1 expression-independent CD3 binding. Although the CD3 binding activity was attenuated compared with that of 1+1, ABL602 2+1 exhibited much stronger T-cell activation and potent tumor-killing activities in AML cell lines. ABL602 2+1 efficiently inhibited tumor progression in subcutaneously and orthotopically engrafted AML mouse models. In the orthotopic mouse model, tumor growth inhibition was observed by gross measurement of luciferase activity, as well as a reduced proportion of AML blasts in the bone marrow, as determined by flow cytometry and immunohistochemistry (IHC) staining. ABL602 2+1 efficiently activated T cells and induced the lysis of AML blasts, even at very low effector:target (E:T) ratios (eg, 1:50). Compared with the reference 1+1 antibody, ABL602 did not induce the release of cytokines including interleukin-6 and tumor necrosis factor-α in the healthy donor-derived peripheral blood mononuclear cell. With its potent tumor-killing activity and reduced cytokine release, ABL602 2+1 is a promising candidate for treating patients with AML and warrants further study.

논문정보

형식Research article
게재일2023년 10월 (BRIC 등록일 2023-10-25)
연구진국내 연구진
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