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2819 Molecular Determinants of Sensitivity to Polatuzumab-Vedotin in Diffuse Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Fundamental Science, Research, Biological therapies, Antibody Therapy, Lymphomas, Translational Research, non-Hodgkin lymphoma, B Cell lymphoma, Diseases, immune mechanism, aggressive lymphoma, Therapies, Lymphoid Malignancies, Biological Processes
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Sean R Corcoran, PhD1,2,3*, Jaewoo Choi, PhD4, Rachel E Fenner1*, Xin Yu4*, Sebastian Scheich, MD5*, Tony Hsiao6*, Galina Schevchenko, PhD1*, Vivian M Morris7*, James D Phelan, PhD4*, Evangelia K Papachristou8*, Kamal Kishore, PhD8*, Clive S D'Santos, PhD9*, Yanlong Ji, PhD10*, Stefania Pittaluga, MD, PhD11*, George Wright12*, Henning Urlaub13*, Kuan-Ting Pan14*, Thomas Oellerich, Prof. MD15*, Jagan R. Muppidi, MD, PhD4*, Daniel James Hodson, MD-PhD16 and Louis M. Staudt, MD, PhD4

1Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
2Boston University Chobanian and Avedisian School of Medicine, Boston, MA
3Lymphoid Malignancies Branch, NIH/NCI, Boston, MA
4Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
5Goethe University, Frankfurt Am Main, DEU
6NIH/NCI, Bethesda
7Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda
8Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
9University of Cambridge, Cambridge, GBR
10Max-Planck-Institute for Multidisciplinary Sciences, Göttingen, Germany
11Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
12Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD
13Max-planck-Institut Für Biophysikalische Chemie, Göttingen, DEU
14MPI For Biophysical Chemistry, Goettingen, DEU
15Goethe University, Frankfurt, DEU
16Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, GBR

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.

Disclosures: Oellerich: Merck KGaA: Honoraria; Roche: Honoraria; Merck KGaA: Research Funding; Gilead: Research Funding.

*signifies non-member of ASH