Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia.

Autor:	Cyr MG; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA.; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida, USA., Mhibik M; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA., Qi J; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Peng H; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Chang J; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Gaglione EM; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA., Eik D; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA., Herrick J; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA., Venables T; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Novick SJ; Department of Molecular Medicine, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Courouble VV; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida, USA.; Department of Molecular Medicine, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Griffin PR; Department of Molecular Medicine, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA., Wiestner A; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA., Rader C; Department of Immunology and Microbiology, UF Scripps Biomedical Research, University of Florida, Jupiter, Florida, USA crader@scripps.edu.; Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida, USA.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Nov; Vol. 10 (11).
DOI:	10.1136/jitc-2022-004850
Abstrakt:	Background: Despite numerous therapeutic options, safe and curative therapy is unavailable for most patients with chronic lymphocytic leukemia (CLL). A drawback of current therapies such as the anti-CD20 monoclonal antibody (mAb) rituximab is the elimination of all healthy B cells, resulting in impaired humoral immunity. We previously reported the identification of a patient-derived, CLL-binding mAb, JML-1, and identified sialic acid-binding immunoglobulin-like lectin-6 (Siglec-6) as the target of JML-1. Although little is known about Siglec-6, it appears to be an attractive target for cancer immunotherapy due to its absence on most healthy cells and tissues. Methods: We used a target-specific approach to mine for additional patient-derived anti-Siglec-6 mAbs. To assess the therapeutic utility of targeting Siglec-6 in the context of CLL, T cell-recruiting bispecific antibodies (T-biAbs) that bind to Siglec-6 and CD3 were engineered into single-chain variable fragment-Fc and dual-affinity retargeting (DART)-Fc constructs. T-biAbs were evaluated for their activity in vitro, ex vivo, and in vivo. Results: We discovered the anti-Siglec-6 mAbs RC-1 and RC-2, which bind with higher affinity than JML-1 yet maintain similar specificity. Both JML-1 and RC-1 T-biAbs were effective at activating T cells and killing Siglec-6 + target cells. The RC-1 clone in the DART-Fc format was the most potent T-biAb tested and was the only anti-Siglec-6 T-biAb that eliminated Siglec-6 + primary CLL cells via autologous T cells at pathological T-to-CLL cell ratios. Tested at healthy T-to-B cell ratios, it also eliminated a Siglec-6 + fraction of primary B cells from healthy donors. The subpicomolar potency of the DART-Fc format was attributed to the reduction in the length and flexibility of the cytolytic synapse. Furthermore, the RC-1 T-biAb was effective at clearing MEC1 CLL cells in vivo and demonstrated a circulatory half-life of over 7 days. Conclusion: Siglec-6-targeting T-biAbs are highly potent and specific for eliminating Siglec-6 + leukemic and healthy B cells while sparing Siglec-6 - healthy B cells, suggesting a unique treatment strategy for CLL with diminished suppression of humoral immunity. Our data corroborate reports that T-biAb efficacy is dependent on synapse geometry and reveal that synapse architecture can be tuned via antibody engineering. Our fully human anti-Siglec-6 antibodies and T-biAbs have potential for cancer immunotherapy. Trial Registration Number: NCT00923507. Competing Interests: Competing interests: CR and MGC are inventors of a patent application for recombinant human antibodies targeting Siglec-6 and their applications. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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