CD300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation.

Edward Abadir,Harry J Iland,Fiona Kupresanin,P Joy Ho,Tsun‐Ho Lo,Adelina Romano,Georgina J Clark,P Mark Hogarth,Pablo A Silveira,Phillip D Fromm,Kenneth Bradstock,Marina L Kennerson,Kaitao Lai,Derek N.J Hart,Robin E Gasiorowski

doi:10.1002/1878-0261.12549

Abstract

Antibody‐based therapy in acute myeloid leukemia (AML) has been marred by significant hematologic toxicity due to targeting of both hematopoietic stem and progenitor cells (HSPCs). Achieving greater success with therapeutic antibodies requires careful characterization of the potential target molecules on AML. One potential target is CD300f, which is an immunoregulatory molecule expressed predominantly on myeloid lineage cells. To confirm the value of CD300f as a leukemic target, we showed that CD300f antibodies bind to AML from 85% of patient samples. While one CD300f monoclonal antibody (mAb) reportedly did not bind healthy hematopoietic stem cells, transcriptomic analysis found that CD300f transcripts are expressed by healthy HSPC. Several CD300f protein isoforms exist as a result of alternative splicing. Importantly for antibody targeting, the extracellular region of CD300f can be present with or without the exon 4‐encoded sequence. This results in CD300f isoforms that are differentially bound by CD300f‐specific antibodies. Furthermore, binding of one mAb, DCR‐2, to CD300f exposes a structural epitope recognized by a second CD300f mAb, UP‐D2. Detailed analysis of publicly available transcriptomic data indicated that CD34+ HSPC expressed fewer CD300f transcripts that lacked exon 4 compared to AML with monocytic differentiation. Analysis of a small cohort of AML cells revealed that the UP‐D2 conformational binding site could be induced in cells from AML patients with monocytic differentiation but not those from other AML or HSPC. This provides the opportunity to develop an antibody‐based strategy to target AMLs with monocytic differentiation but not healthy CD34+ HSPCs. This would be a major step forward in developing effective anti‐AML therapeutic antibodies with reduced hematologic toxicity.

Highlights

Intensive chemotherapy with or without allogeneic hematopoietic cell transplant cures a proportion of younger patients diagnosed with acute myeloid leukemia (AML); these therapies are too toxic for the majority of patients (Juliusson et al, 2009)
There was no significant difference between the ability of UP-D1 and anti-CD33 to bind total AML blasts or the CD34+CD38À subset, which is enriched with leukemic stem cells (Fig. 1A,B)
UP-D1 bound to the Lin-CD34+CD38ÀCD45RA-CD90+ hematopoietic stem cell (HSC) precursor population within healthy bone marrow (BM) (Fig. 1C) similar to CD33

Summary

Introduction

Intensive chemotherapy with or without allogeneic hematopoietic cell transplant cures a proportion of younger patients diagnosed with AML; these therapies are too toxic for the majority of patients (Juliusson et al, 2009). Acute myelomonocytic leukemia AMLs account for 5–10% of cases across all age groups with a median age of 50 years, while acute monocytic/monoblastic leukemia AMLs occur in any age range but are most common in children (Swerdlow et al, 2008). Together, these AML subtypes account for 50% of all AMLs in infants (Masetti et al, 2015). A new targeted therapy with reduced hematologic toxicity in AML with monocytic differentiation, including acute myelomonocytic leukemia as well as acute monoblastic and monocytic leukemia, would be a significant development

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Conclusion