The tetravalent, bispecific properties of FS118, an anti-LAG-3/PD-L1 antibody, mediate LAG-3 shedding from CD4+ and CD8+ tumor-infiltrating lymphocytes.

 0 Người đánh giá. Xếp hạng trung bình 0

Tác giả: Neil Brewis, Wenjia Liao, Michelle Morrow, Beatrice J Potter-Landua, Claire S Reader, Claire J Seal, Christel Séguy Veyssier

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: England : Anti-cancer drugs , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 180311

Tumor-infiltrating lymphocytes (TILs) often have upregulated expression of immune checkpoint receptors, such as programmed cell death 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3). Patients treated with antibodies targeting PD-1 or its ligand (PD-L1) can develop resistance or relapse, with LAG-3 upregulation on T cells being one possible mechanism. FS118 is a tetravalent, bispecific antibody comprising a full-length IgG1 anti-PD-L1 antibody with bivalent LAG-3-binding capability in the fragment crystallizable region. Here we demonstrate how the structure of FS118 is important for its function. We generated variants of FS118 and tested their ability to mediate LAG-3 shedding using staphylococcal enterotoxin B assays, antigen recall assays, and soluble LAG-3 ELISAs. Mediated by metalloproteases ADAM10 and ADAM17, FS118 induced shedding of LAG-3 from the surface of both CD4+ and CD8+ T cells. We also determined the effect of surrogate antibodies on immune cell LAG-3 expression and proliferation in syngeneic mouse models. In vivo, the bivalent LAG-3 binding sites of a mouse surrogate of FS118 and their location in the fragment crystallizable region were important for eliciting maximal reduction in LAG-3 levels on the surface of TILs, as variants with a single LAG-3 binding site in the fragment crystallizable region, or with reversed orientation of the LAG-3 and PD-L1 binding sites, were less efficient at inducing shedding. We also show that PD-L1, not PD-1, binding drives the LAG-3 reduction on TILs. We hypothesize that the LAG-3 bivalency in the fragment crystallizable region of FS118 allows LAG-3 clustering, which optimizes cleavage by ADAM10/ADAM17 and thus shedding.
Tạo bộ sưu tập với mã QR

THƯ VIỆN - TRƯỜNG ĐẠI HỌC CÔNG NGHỆ TP.HCM

ĐT: (028) 36225755 | Email: tt.thuvien@hutech.edu.vn

Copyright @2024 THƯ VIỆN HUTECH