한빛사논문
Seil Janga,b,f, Jaeho Songb, NaYoung Kimb, Jeonghyeon Bakb, Keehoon Jungc, Young Woo Parkb, Bum-Chan Parkb,*, Ho Min Kima,d,e,*
aBiomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea
bY-BIOLOGICS, Inc., 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Korea
cSeoul National University College of Medicine, Seoul 03080, Korea
dGraduate School of Medical Science & Engineering, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Korea
eCenter for Biomolecular & Cellular Structure, Institute for Basic Science (IBS), Daejeon 34126, Korea
fCTCELLS, Inc., R7, 333 Techno Jungang-daero, Hyeonpung-eup, Dalseong-gun, Daegu 42988, Korea
*Corresponding author.
Abstract
Following the clinical success of immunotherapeutic antibodies, bispecific antibodies for cytotoxic effector cell redirection, tumor-targeted immunomodulation and dual immunomodulation, have received particular attentions. Here, we developed a novel bispecific antibody platform, termed Antibody-Like Cell Engager (ALiCE), wherein the Fc domain of each heavy chain of immunoglobulin G (IgG) is replaced by the VH and VL domains of an IgG specific to a second antigen while retaining the N-terminal Fab of the parent antibody. Because of specific interactions between the substituted VH and VL domains, the C-terminal stem Fv enables ALiCE to assemble autonomously into hetero-tetramers, thus simultaneously binding to two distinct antigens but with different avidities. This design strategy was used to generate ACE-05 (two anti-PD-L1 Fab × anti-CD3 Fv) and ACE-31 (two anti-CD3 Fab × anti-PD-L1 Fv), both of which bound PD-L1 and CD3. However, ACE-05 was more effective than ACE-31 in reducing off-target toxicity caused by the indiscriminate activation of T cells. Moreover, in cell-based assays and PBMC-reconstituted humanized mice harboring human non-small-cell lung cancer tumors, ACE-05 showed marked antitumor efficacy, causing complete tumor regression at a dose of 0.05 mg/kg body weight. The dual roles of ACE-05 in immune checkpoint inhibition and T-cell redirection, coupled with reduced off-target toxicity, suggest that ACE-05 may be a promising anti-cancer therapeutic agent. Moreover, the bispecific ALiCE platform can be further used for tumor-targeted or multiple immunomodulation applications.
Keywords : Antibody-engineering, Bispecific Antibody, T-cell engager, Cancer immunotherapy
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