CD37 in Acute Myeloid Leukemia: a Novel Surface Target for Drug Delivery

Overview

Journal Blood Adv

Specialty Hematology

Date 2024 Sep 30

PMID 39348689

Authors

Erin Jeremy

Esthela Artiga

Sara Elgamal

Carolyn Cheney

Dalen Eicher

Kevan Zalponik

Shelley Orwick

Charlene Mao

Ronni Wasmuth

Bonnie Harrington

Allison Mustonen

Peter Beshay

Patrick Halley

Carlos Castro

Katie Williams

Zachary Hing

Timothy Chen

Christopher Lucas

Nicholas J Vantangoli

Rosa Lapalombella

Nicole Grieselhuber

Xiaokui Mo

Erin Hertlein

Natarajan Muthusamy

Bethany L Mundy-Bosse

John C Byrd

Karilyn T Larkin

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukemia (AML) is the most common and lethal leukemia in adults. AML consists of many genetic subtypes, which limits broad applicability of targeted therapy. We discovered that the hematopoiesis-restricted tetraspanin CD37 is expressed on the majority of primary AML blasts and thus may represent a common therapeutic target for AML regardless of subtype. We demonstrate that the internalization properties of CD37 are distinct in AML blasts when compared with normal blood cells, and that CD37 rapidly accumulates inside AML blasts via dynamin-dependent endocytosis. Our work revealed that the clinically relevant anti-CD37 antibody-drug conjugate (ADC) Debio 1562 (αCD37-DM1) is highly cytotoxic to AML blasts, but not normal hematopoietic stem cells. We found that αCD37-DM1 improved clinical outcomes and overall survival in multiple in vivo models of AML. Together, these data demonstrate that targeting CD37 with an ADC such as αCD37-DM1 is a feasible and promising therapeutic option for the treatment of AML.

References

Paul M, Weller M . Antibody Screening by Microarray Technology-Direct Identification of Selective High-Affinity Clones. Antibodies (Basel). 2020; 9(1). PMC: 7175374. DOI: 10.3390/antib9010001. View

Bobrowicz M, Kubacz M, Slusarczyk A, Winiarska M . CD37 in B Cell Derived Tumors-More than Just a Docking Point for Monoclonal Antibodies. Int J Mol Sci. 2020; 21(24). PMC: 7765243. DOI: 10.3390/ijms21249531. View

Beckwith K, Byrd J, Muthusamy N . Tetraspanins as therapeutic targets in hematological malignancy: a concise review. Front Physiol. 2015; 6:91. PMC: 4369647. DOI: 10.3389/fphys.2015.00091. View

Sacks N, Cyr P, Louie A, Liu Y, Chiarella M, Sharma A . Burden of Acute Myeloid Leukemia Among Older, Newly Diagnosed Patients: Retrospective Analysis of Data From the 2010-2012 Medicare Limited Data Set. Clin Ther. 2018; 40(5):692-703.e2. DOI: 10.1016/j.clinthera.2018.03.012. View

Walter R, Raden B, Kamikura D, Cooper J, Bernstein I . Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood. 2004; 105(3):1295-302. DOI: 10.1182/blood-2004-07-2784. View

Pereira D, Guevara C, Jin L, Mbong N, Verlinsky A, Hsu S . AGS67E, an Anti-CD37 Monomethyl Auristatin E Antibody-Drug Conjugate as a Potential Therapeutic for B/T-Cell Malignancies and AML: A New Role for CD37 in AML. Mol Cancer Ther. 2015; 14(7):1650-60. PMC: 4557793. DOI: 10.1158/1535-7163.MCT-15-0067. View

Lichtman M . Interrupting the inhibiton of normal hematopoiesis in myelogenous leukemia: a hypothetical approach to therapy. Stem Cells. 2000; 18(5):304-6. DOI: 10.1634/stemcells.18-5-304. View

Aubrey B, Kelly G, Kueh A, Brennan M, OConnor L, Milla L . An inducible lentiviral guide RNA platform enables the identification of tumor-essential genes and tumor-promoting mutations in vivo. Cell Rep. 2015; 10(8):1422-32. DOI: 10.1016/j.celrep.2015.02.002. View

Ley T, Miller C, Ding L, Raphael B, Mungall A, Robertson A . Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368(22):2059-74. PMC: 3767041. DOI: 10.1056/NEJMoa1301689. View

Stathis A, Flinn I, Madan S, Maddocks K, Freedman A, Weitman S . Safety, tolerability, and preliminary activity of IMGN529, a CD37-targeted antibody-drug conjugate, in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: a dose-escalation, phase I study. Invest New Drugs. 2018; 36(5):869-876. PMC: 6153548. DOI: 10.1007/s10637-018-0570-4. View

10.

Caulier B, Joaquina S, Gelebart P, Dowling T, Kaveh F, Thomas M . CD37 is a safe chimeric antigen receptor target to treat acute myeloid leukemia. Cell Rep Med. 2024; 5(6):101572. PMC: 11228397. DOI: 10.1016/j.xcrm.2024.101572. View

11.

Hemler M . Specific tetraspanin functions. J Cell Biol. 2002; 155(7):1103-7. PMC: 2199333. DOI: 10.1083/jcb.200108061. View

12.

McCluskey A, Daniel J, Hadzic G, Chau N, Clayton E, Mariana A . Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis. Traffic. 2013; 14(12):1272-89. PMC: 4138991. DOI: 10.1111/tra.12119. View

13.

Medeiros B, Satram-Hoang S, Hurst D, Hoang K, Momin F, Reyes C . Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015; 94(7):1127-38. PMC: 4432101. DOI: 10.1007/s00277-015-2351-x. View

14.

Remillard S, REBHUN L, Howie G, Kupchan S . Antimitotic activity of the potent tumor inhibitor maytansine. Science. 1975; 189(4207):1002-5. DOI: 10.1126/science.1241159. View

15.

Jager P, Geyh S, Twarock S, Cadeddu R, Rabes P, Koch A . Acute myeloid leukemia-induced functional inhibition of healthy CD34+ hematopoietic stem and progenitor cells. Stem Cells. 2021; 39(9):1270-1284. DOI: 10.1002/stem.3387. View

16.

Eisfeld A, Kohlschmidt J, Mrozek K, Volinia S, Blachly J, Nicolet D . Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Res. 2016; 77(1):207-218. PMC: 5215102. DOI: 10.1158/0008-5472.CAN-16-1386. View

17.

Lapalombella R, Yeh Y, Wang L, Ramanunni A, Rafiq S, Jha S . Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals. Cancer Cell. 2012; 21(5):694-708. PMC: 3360882. DOI: 10.1016/j.ccr.2012.03.040. View

18.

Chari R . Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2007; 41(1):98-107. DOI: 10.1021/ar700108g. View

19.

Walter R, Appelbaum F, Estey E, Bernstein I . Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood. 2012; 119(26):6198-208. PMC: 3383202. DOI: 10.1182/blood-2011-11-325050. View