Development of an antibody-like T-cell engager based on VH-VL heterodimer formation and its application in cancer therapy

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dc.contributor.authorJang, Seilko
dc.contributor.authorSong, Jaehoko
dc.contributor.authorKim, NaYoungko
dc.contributor.authorBak, Jeonghyeonko
dc.contributor.authorJung, Keehoonko
dc.contributor.authorPark, Young Wooko
dc.contributor.authorPark, Bum-Chanko
dc.contributor.authorKim, Ho Minko
dc.date.accessioned2021-05-18T01:10:10Z-
dc.date.available2021-05-18T01:10:10Z-
dc.date.created2021-05-17-
dc.date.created2021-05-17-
dc.date.created2021-05-17-
dc.date.created2021-05-17-
dc.date.created2021-05-17-
dc.date.issued2021-04-
dc.identifier.citationBIOMATERIALS, v.271-
dc.identifier.issn0142-9612-
dc.identifier.urihttp://hdl.handle.net/10203/285270-
dc.description.abstractFollowing 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.-
dc.languageEnglish-
dc.publisherELSEVIER SCI LTD-
dc.titleDevelopment of an antibody-like T-cell engager based on VH-VL heterodimer formation and its application in cancer therapy-
dc.typeArticle-
dc.identifier.wosid000639774500002-
dc.identifier.scopusid2-s2.0-85103125760-
dc.type.rimsART-
dc.citation.volume271-
dc.citation.publicationnameBIOMATERIALS-
dc.identifier.doi10.1016/j.biomaterials.2021.120760-
dc.contributor.localauthorKim, Ho Min-
dc.contributor.nonIdAuthorSong, Jaeho-
dc.contributor.nonIdAuthorKim, NaYoung-
dc.contributor.nonIdAuthorBak, Jeonghyeon-
dc.contributor.nonIdAuthorJung, Keehoon-
dc.contributor.nonIdAuthorPark, Young Woo-
dc.contributor.nonIdAuthorPark, Bum-Chan-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorAntibody-engineering-
dc.subject.keywordAuthorBispecific antibody-
dc.subject.keywordAuthorT-cell engager-
dc.subject.keywordAuthorCancer immunotherapy-
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