CD123-Directed Bispecific Antibodies for Targeting MDS Clones and Immunosuppressive Myeloid-Derived Suppressor Cells (MDSC) in High-Risk Adult MDS Patients.

Fatih M Uckun,Justin Watts

doi:10.3389/fragi.2021.757276

Abstract

There is an urgent need to identify effective strategies to prevent leukemic transformation and induce sustained deep remissions in adult high-risk myelodysplastic syndrome (MDS) patients. This article discusses the clinical impact potential of bispecific antibodies (BiAB) capable of redirecting host T-cell cytotoxicity in an MHC-independent manner to malignant clones as well as immunosuppressive myeloid-derived suppressor cells (MDSC) as a new class of anti-MDS drug candidates. T-cell engaging BiAB targeting the CD123 antigen may help delay disease progression in high-risk adult MDS and potentially reduce the risk of transformation to secondary AML.

Highlights

Adult myelodysplastic syndrome (MDS), a heterogeneous group of clonal malignant hematologic disorders with an incidence rate of 4.5 per 100,000 persons per year, is characterized by ineffective hematopoiesis, abnormal differentiation of progenitor cells in the myeloid, erythroid, and megakaryocytic compartments, emergence of dysplastic myeloid cells, and an enhanced risk of transformation to acute myeloid leukemia (AML) (National Cancer Institute, 2016; National Cancer Institute, 2021; Zhan and Park, 2021)
The immunosuppressive bone marrow microenvironment (BMME) in adult MDS has been implicated in clonal evolution and disease progression (Sallman and List, 2019; Younos et al, 2015; Chen et al, 2013; Gañán-Gómez et al, 2015)
Expanded populations of myeloid-derived suppressor cells (MDSC), representing CD33+CD123+ immature myeloid cells within the bone marrow mononuclear cell fraction contribute to the immunosuppressive tumor microenvironment

Summary

INTRODUCTION

Adult myelodysplastic syndrome (MDS), a heterogeneous group of clonal malignant hematologic disorders with an incidence rate of 4.5 per 100,000 persons per year, is characterized by ineffective hematopoiesis, abnormal differentiation of progenitor cells in the myeloid, erythroid, and megakaryocytic compartments, emergence of dysplastic myeloid cells, and an enhanced risk of transformation to acute myeloid leukemia (AML) (National Cancer Institute, 2016; National Cancer Institute, 2021; Zhan and Park, 2021). In a Phase 1 study in therapy-refractory adult AML and high-risk adult MDS patients (NCT02152956), this CD3-engaging bispecific antibody exhibited promising single agent activity with an overall composite response rate of 30% (Uy et al, 2017). To determine the maximum tolerated dose (MTD) of SAR440234 administered as a single agent in patients with R/R AML (relapsed or refractory acute myeloid leukemia), HR-MDS (high risk myelodysplastic syndrome), or B-ALL (B-cell acute lymphoblastic leukemia), and determine the recommended phase 2 dose (RP2D) for the subsequent Expansion part. NCT02152956 A phase I/II, First in Human, Dose I/II Escalation Study of MGD006, a CD123 × CD3 Dual Affinity Retargeting (DART®) Bi-Specific Antibody Based Molecule, in Patients With Relapsed or Refractory AML or Intermediate-2/ High Risk MDS. APVO436-related CRS was not required for clinically meaningful responses in R/R AML

DISCUSSION

CONCLUSION