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Identification of proteins that interact with Siglec-6

ABSTRACT: Siglec-6 is a glycoprotein overexpressed on chronic lymphocytic leukemia (CLL) cell. We have shown that Siglec-6 promotes migration and adhesion of CLL cells towards CLL bone marrow stromal cells. To elucidate the mechanistic pathway involved in Siglec-6 dependent migration, we performed mass spectrometry proteomics analysis on MEC1-002 CLL cell line pulled down with a Siglec-6 targeted antibody, which revealed that Siglec-6 interacts with DOCK8, a guanine nucleotide exchange factor. Interaction of Siglec-6 with its ligand promotes DOCK8 dependent Cdc42 activation, WASP protein recruitment and F-actin polymerization. Therapeutically, Siglec-6 leukemic cells can be eliminated with a Siglec-6 targeted bispecific antibody in vitro and in vivo.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): Chronic Lymphocytic Leukemia

SUBMITTER: Jessica Nunes

LAB HEAD: Natarajan Muthusamy

PROVIDER: PXD039892 | Pride | 2024-05-08

REPOSITORIES: Pride

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			Action	DRS
	33978_ISO_1_6uL.raw	Raw
	33978_ISO_1_F005619.dat	Other
	33978_ISO_2_6uL.raw	Raw
	33978_ISO_2_F005623.dat	Other
	33978_ISO_3_6uL.raw	Raw

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Project description:Despite numerous therapeutic options, safe and curative therapy is out of reach for most chronic lymphocytic leukemia (CLL) patients. We previously reported the identification of a patient-derived CLL-binding antibody, JML-1, and identified Siglec-6 as the target of JML-1. Siglec-6 is an attractive target for cancer immunotherapy due to its absence on healthy tissues and potential role in immune signaling. In this work, we identify additional patient-derived anti-Siglec-6 antibodies, RC-1 and RC-2, that bind with higher affinity than JML-1, yet exhibit similar specificity and overlapping conformational epitopes. Both JML-1 and RC-1 were employed to generate anti-Siglec-6 x anti-CD3 T cell-recruiting bispecific antibodies (T-biAbs) which were effective in vitro at activating T cells and lysing target cells. Upon engineering RC-1 into more compact and rigid T-biAb formats, we achieved sub-pM EC50 values for cell lysis in vitro. In addition, the T-biAbs mediated the killing of primary CLL cells by autologous T cells at natural effector-to-target cell ratios ex vivo. The increased potency of this T-biAb format appears to be due to the reduction in the length and/or flexibility of the cytolytic synapse. Furthermore, the anti-Siglec-6 x anti-CD3 T-biAb was effective at curing mice in a systemic in vivo model of CLL.

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