Antibody therapies for the treatment of acute myeloid leukemia: exploring current and emerging therapeutic targets

Abstract

Introduction: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients.

Areas covered: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials.

Expert opinion: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions.

Keywords: Acute myeloid leukemia; CD33; CD47; LILRB4; antibody; antibody-drug conjugate; bispecific antibody; fusion protein; immunotherapy; targeted therapy.

Figure 1.. Overview of receptor targets for antibody-based therapy in acute myeloid leukemia (AML) patients.

The receptors shown on the surface of the “AML” cell are currently in pre-clinical and clinical studies as targets for antibody-based therapy of AML myeloblasts and leukemic stem cells. The receptors illustrated on the surface of DCs, NK cells and T cells are targets for multispecific antibody-based therapies that directly crosslink these immune cells to AML myeloblasts and leukemic stem cells, leading to potentiation of antigen-presentation and immune effector function against the malignant cells. Created with BioRender.com.

Figure 2.. LILRB4 signaling in the acute myeloid leukemia (AML) immune and stromal tumor microenvironment (TME).

LILRB4 on AML cells binds Apolipoprotein E (ApoE) and this recruits SHP-2 leading to upregulation of NFκB and induction of downstream effectors including arginase 1 (ARG1) and urokinase receptor (uPAR) which inhibit T cell proliferation and promote tissue infiltration respectively. Additionally, fibronectin serves as a ligand for LILRB4 on myeloid cells in the stromal TME supporting phenotypic differentiation into tumor-associated suppressive cells such as tolerogenic dendritic cells that downregulate inflammatory signaling leading to failure of leukocyte adhesion and local T cell suppression. Created with BioRender.com.

Figure 3.. Mechanisms of antibody-based therapeutics targeting LILRB4 in acute myeloid leukemia (AML).

Unconjugated antagonistic antibodies against LILRB4 prevent binding of its ApoE and fibronectin ligands, leading to disinhibition of T cell proliferation and suppression of anti-inflammatory myeloid cell differentiation while simultaneously prohibiting migration of LILRB4⁺ tumor cells to distant sites. Humanized anti-LILRB4 mAbs in an IgG₁ format with intact, functional Fc can also engage effector NK cells and macrophages in antibody dependent cell-mediated cytotoxicity and phagocytosis respectively. Furthermore, as LILRB4 is significantly overexpressed on monocytic AML cells, cytotoxic antibody-derived therapeutics targeting LILRB4 such as anti-LILRB4 chimeric antigen receptor (CAR) T cells and anti-LILRB4 antibody-drug conjugates (ADCs) have been developed that have shown great efficacy against monocytic AML subtypes. Created with BioRender.com.

Figure 4.. Bispecific antibody-based immune cell engager (ICE) formats commonly used to target acute myeloid leukemia (AML).

Bispecific antibody-based therapeutic formats commonly used to target AML can be broadly classified into Non-IgG-Like ICEs lacking an IgG Fc and IgG-Like ICEs containing a Fc domain. The Non-IgG-Like BiTE is made up of a scFv targeting a leukemia-specific antigen (LSA) linked to a scFv targeting a T cell antigen, typically CD3. A Non-IgG-Like DART bispecific agent consists of variable domains of two antigen binding specificities linked to two independent polypeptide chains connected noncovalently. There is also an additional covalent linker in the form of a disulfide bridge, enhancing stability and promoting efficient crosslinking of AML and T cells. The TandAb is a Non-IgG-Like bispecific ICE with improved avidity through its bivalent binding of both the LSA and T cell antigen. The IgG-Like ICE class has superior stability via its Fc domain which can bind neonatal Fc receptors in vascular endothelial cells, preventing lysosomal degradation of these bsAbs. This class contains the heterodimeric Asymmetric IgGs which appear similar to conventional homodimeric IgG antibodies but have two structurally different Fab arms which bind to LSAs and T cell antigens respectively. The IgG-Like BiTE (Half Life Extended) is simply a BiTE fused to an IgG Fc domain to improve serum half-life of the compound. The IgG-Like Fab-scFv-Fc is a heterodimeric antibody-like protein with an LSA-targeting Fab arm and T cell antigen-targeting scFv fused to a Fc domain. And the IgG-Like scFv2-Fc-scFv2 and IgG(H)-scFv2 bispecifics each leverage bivalent formats to increase avidity to their target antigens. The former incorporates two LSA-targeting scFvs fused to the N-terminus and two T cell antigen-targeting scFvs fused to the C-terminus of an IgG Fc domain, while the latter is a canonical IgG antibody fused to two T cell antigen-targeting scFvs at the Fc C-terminus. Created with BioRender.com.