表位
癌症研究
抗体-药物偶联物
弥漫性大B细胞淋巴瘤
体内
抗原
唾液酸
抗体
淋巴瘤
生物
免疫学
化学
医学
单克隆抗体
遗传学
作者
Sean Corcoran,Jaewoo Choi,Rachel E Fenner,Xin Yu,Sebastian Scheich,Tony Hsiao,Galina Schevchenko,Vivian Morris,James D. Phelan,Evangelia K. Papachristou,Kamal Kishore,Clive S. D’Santos,Yanlong Ji,Stefania Pittaluga,George W. Wright,Henning Urlaub,Kuan-Ting Pan,Thomas Oellerich,Jagan R. Muppidi,Daniel J. Hodson,Louis M. Staudt
出处
期刊:Blood
[American Society of Hematology]
日期:2023-11-28
卷期号:142 (Supplement 1): 2819-2819
标识
DOI:10.1182/blood-2023-178059
摘要
Purpose: Polatuzumab Vedotin (Pola-V) is an antibody-drug conjugate directed to the B cell surface antigen CD79B. When combined with conventional immunochemotherapy, Pola-V improves outcomes in DLBCL overall; however, there is noted heterogeneity in response to Pola-V, with germinal center b-cell (GCB) DLBCL showing no added benefit to the addition of Pola-V compared to standard immunochemotherapy. We aimed to identify molecular determinants of sensitivity or resistance to Pola-V. We hypothesized that these might lead us to innovative strategies to improve on-target tumor killing by Pola-V, or to find novel biomarkers that predict drug resistance. Methods: We employed combined drug-sensitization and CD79B-sorted CRISPR-Cas9 screening to identify molecular determinants of sensitivity to CD79B-directed, tumor killing by Pola-V in 9 cell lines representing different molecular subtypes of DLBCL. Results: Our results reveal the striking impact of epitope glycosylation, specifically a2,6 sialylation, on the binding of Pola-V to CD79B and thereby its ability to kill tumor cells. Specifically, we identify the exact glycosylated residues on CD79A and CD79B which create a glycan shield around the Pola-V binding site, precluding binding to its target. We show how genetic, pharmacological and enzymatic approaches that remove terminal sialic acid residues from these N-linked glycans lead to enhanced tumor killing by Pola-V. We hypothesize and test multiple methods of targeting this pathway in order to enhance Pola-V killing both in vitro and in vivo. Finally, we reveal a previously unappreciated role for the ubiquitin ligase KLHL6 in regulating CD79B protein abundance and surface expression of the B cell antigen receptor (BCR), including how this pathway is used by physiological germinal center B cells and how it is corrupted to enhance BCR expression in GCB DLBCL. Conclusions: These findings unravel the molecular basis of response heterogeneity to Pola-V and identify approaches that might be deployed therapeutically to enhance the efficacy of CD79B-specific tumor killing. In addition, we identify how KLHL6 determines expression of the BCR in both physiological and malignant germinal center B cells, and how KLHL6 mutation may modulate sensitivity of GCB DLBCL tumors to Pola-V.
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