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

• DOI: 10.1136/jitc-2022-004850
• Publication Date: 2022-11-28T15:00:51Z
• Authors: Matthew G Cyr; Maissa Mhibik; Junpeng Qi; Haiyong Peng; Jing Chang; Erika M Gaglione; David Eik; John Herrick; Thomas Venables; Scott J Novick; Valentine V Couro...; Patrick R Griffin; Adrian Wiestner; Christoph Rader
• Keywords: SIGLEC

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 elimination all healthy B cells, resulting in impaired humoral immunity. We previously reported identification a patient-derived, CLL-binding mAb, JML-1, identified sialic acid-binding immunoglobulin-like lectin-6 (Siglec-6) target JML-1. Although little known about Siglec-6, it appears to be an attractive cancer immunotherapy due its absence on cells tissues. used target-specific approach mine additional patient-derived anti-Siglec-6 mAbs. To assess utility targeting Siglec-6 context CLL, T cell-recruiting bispecific antibodies (T-biAbs) that bind CD3 were engineered into single-chain variable fragment-Fc dual-affinity retargeting (DART)-Fc constructs. T-biAbs evaluated their activity vitro, ex vivo, vivo. discovered mAbs RC-1 RC-2, which higher affinity than JML-1 yet maintain similar specificity. Both effective at activating killing Siglec-6+ cells. The clone DART-Fc format was potent T-biAb tested only eliminated primary CLL via autologous pathological T-to-CLL cell ratios. Tested T-to-B ratios, also fraction from donors. subpicomolar potency attributed reduction length flexibility cytolytic synapse. Furthermore, clearing MEC1 vivo demonstrated circulatory half-life over 7 days. Siglec-6-targeting are highly specific eliminating leukemic while sparing Siglec-6- suggesting unique treatment strategy diminished suppression Our data corroborate reports efficacy dependent synapse geometry reveal architecture can tuned engineering. fully human have potential immunotherapy. NCT00923507.