PXD029601-2

PXD029601 is an original dataset announced via ProteomeXchange.

Title	Patient-derived anti-Siglec-6 antibodies engineered into T cell-recruiting bispecific antibody formats for treating leukemia
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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:30:28.232.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Valentine Courouble
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-05 13:20:20	ID requested
1	2022-12-19 11:35:20	announced
⏵ 2	2023-11-14 08:30:29	announced	2023-11-14: Updated project metadata.

Cyr MG, Mhibik M, Qi J, Peng H, Chang J, Gaglione EM, Eik D, Herrick J, Venables T, Novick SJ, Courouble VV, Griffin PR, Wiestner A, Rader C, Patient-derived Siglec-6-targeting antibodies engineered for T-cell recruitment have potential therapeutic utility in chronic lymphocytic leukemia. J Immunother Cancer, 10(11):(2022) [pubmed]

submitter keyword: Siglec-6,Antibody, HDX-MS

Christoph Rader
contact affiliation	Department of Microbiology and Immunology, The Scripps Research Institute; Jupiter, FL, USA
contact email	crader@scripps.edu
lab head
Valentine Courouble
contact affiliation	Scripps Research
contact email	vcouroub@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/12/PXD029601

PRIDE project URI

• PRIDE
  1. PXD029601
     1. Label: PRIDE project
     2. Name: Patient-derived anti-Siglec-6 antibodies engineered into T cell-recruiting bispecific antibody formats for treating leukemia