دورية أكاديمية
أعرض في EDS

BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells.

التفاصيل البيبلوغرافية
العنوان: BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells.
المؤلفون: van Helden MJ; Byondis BV, Nijmegen, Gelderland, The Netherlands., Zwarthoff SA; Byondis BV, Nijmegen, Gelderland, The Netherlands., Arends RJ; Byondis BV, Nijmegen, Gelderland, The Netherlands., Reinieren-Beeren IMJ; Byondis BV, Nijmegen, Gelderland, The Netherlands., Paradé MCBC; Byondis BV, Nijmegen, Gelderland, The Netherlands., Driessen-Engels L; Byondis BV, Nijmegen, Gelderland, The Netherlands., de Laat-Arts K; Byondis BV, Nijmegen, Gelderland, The Netherlands., Damming D; Byondis BV, Nijmegen, Gelderland, The Netherlands., Santegoeds-Lenssen EWH; Byondis BV, Nijmegen, Gelderland, The Netherlands., van Kuppeveld DWJ; Byondis BV, Nijmegen, Gelderland, The Netherlands., Lodewijks I; Byondis BV, Nijmegen, Gelderland, The Netherlands., Olsman H; Sanquin Research, Amsterdam, The Netherlands., Matlung HL; Sanquin Research, Amsterdam, The Netherlands., Franke K; Sanquin Research, Amsterdam, The Netherlands., Mattaar-Hepp E; Byondis BV, Nijmegen, Gelderland, The Netherlands., Stokman MEM; Byondis BV, Nijmegen, Gelderland, The Netherlands., de Wit B; Byondis BV, Nijmegen, Gelderland, The Netherlands., Glaudemans DHRF; Byondis BV, Nijmegen, Gelderland, The Netherlands., van Wijk DEJW; Byondis BV, Nijmegen, Gelderland, The Netherlands., Joosten-Stoffels L; Byondis BV, Nijmegen, Gelderland, The Netherlands., Schouten J; Byondis BV, Nijmegen, Gelderland, The Netherlands., Boersema PJ; Byondis BV, Nijmegen, Gelderland, The Netherlands., van der Vleuten M; Byondis BV, Nijmegen, Gelderland, The Netherlands., Sanderink JWH; Byondis BV, Nijmegen, Gelderland, The Netherlands., Kappers WA; Byondis BV, Nijmegen, Gelderland, The Netherlands., van den Dobbelsteen D; Byondis BV, Nijmegen, Gelderland, The Netherlands., Timmers M; Byondis BV, Nijmegen, Gelderland, The Netherlands., Ubink R; Byondis BV, Nijmegen, Gelderland, The Netherlands., Rouwendal GJA; Byondis BV, Nijmegen, Gelderland, The Netherlands., Verheijden G; Byondis BV, Nijmegen, Gelderland, The Netherlands., van der Lee MMC; Byondis BV, Nijmegen, Gelderland, The Netherlands., Dokter WHA; Byondis BV, Nijmegen, Gelderland, The Netherlands., van den Berg TK; Byondis BV, Nijmegen, Gelderland, The Netherlands Timo.vandenBerg@byondis.com.; Sanquin Research, Amsterdam, The Netherlands.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Apr; Vol. 11 (4).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-
مواضيع طبية MeSH: CD47 Antigen* , Neoplasms*/drug therapy, Mice ; Animals ; Humans ; T-Lymphocytes/metabolism ; Rituximab ; Macrophages ; Antibodies, Neoplasm
مستخلص: Background: Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.
Method: We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.
Results: BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPα BIT transgenic mice. Finally, BYON4228 shows a favorable safety profile in cynomolgus monkeys.
Conclusions: Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023.
Competing Interests: Competing interests: TKvdB is inventor on WO 2009/131453; GV, GJAR, RJA, TKvdB, HLM and KF are inventors on WO 2018/210793; GV is inventor on WO 2020/099653.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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فهرسة مساهمة: Keywords: combined modality therapy; immunity, innate; immunotherapy; macrophages; receptors, immunologic
المشرفين على المادة: 0 (CD47 Antigen)
4F4X42SYQ6 (Rituximab)
0 (Antibodies, Neoplasm)
تواريخ الأحداث: Date Created: 20230417 Date Completed: 20230419 Latest Revision: 20230626
رمز التحديث: 20230626
مُعرف محوري في PubMed: PMC10186489
DOI: 10.1136/jitc-2022-006567
PMID: 37068796
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2022-006567