https://orcid.org/0000-0002-9834-1975
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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.
Article highlights
Acute myeloid leukemia (AML) is the most common and deadly adult leukemia.
AML is managed with toxic non-targeted chemotherapy and hematopoietic stem cell transplant in patients who can tolerate it.
Older patients can be treated with more benign hypomethylating agents (HMAs) and venetoclax but most patients experience lethal relapsing disease.
Target receptors (e.g. CD33, CD123, CD47, LILRB4) on the AML cell surface have been identified in recent years and antibody-based therapeutics specifically targeting these receptors have shown promise in pre-clinical and clinical studies.
Antibody-based therapeutics have been designed to specifically agonize or antagonize cell signaling pathways downstream of these receptors. They can also be engineered to deliver cytotoxic payloads as antibody-drug conjugates and connect humoral immunity to cell-based cytotoxic immune functions through engineering of the antibody Fc region.
Additionally, bispecific antibody-based therapeutics have been developed to specifically bind effector immune cells such as T cells and NK cells and direct them to malignant cells via concurrent specific binding of tumor-specific antigens.
Continued research into novel AML-specific targets and their fundamental biological functions will aid development of rationally designed antibody-based therapeutics that will provide safer and more effective treatment options for all AML patients.
This box summarizes key points contained in the article.
Acknowledgment
We thank Drs. Charlene Liao and Paul Woodard for their careful and critical editing of the manuscript.
Declaration of interest
N Zhang., Z An and CC Zhang had several patent applications licensed to Immune-Onc Therapeutics, Inc. Z An is a Scientific Advisory Board (SAB) member with Immune-Onc Therapeutics, Inc. NG Daver has received research funding from BMS, Pfizer, Immunogen, NovImmune, Genentech, AbbVie, Astellas, Daiichi-Sankyo, Hanmi, Roche and Forty-Seven, and serves as a consultant/advisor to Pfizer, BMS, Amgen, Gilead, Forty-Seven, Genentech, Novartis, Jazz, Immunogen, Astellas, Abbvie, Genentech, Trillium, Syndax and Kite. CD DiNardo has received research funding (to institution) from AbbVie, Astex, BMS, Cleave, Foghorn, Immune-Onc Therapeutics, Inc., Loxo and Servier, serves as a consultant/advisor to AbbVie, BMS, Genmab, Gilead, GSK, Jazz, Kura, Novartis, Servier and Takeda, and is on the scientific advisory board of Notable Labs.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Abbreviations
ACT: adoptive cellular therapy; ADC: antibody drug conjugate; ADCC: antibody dependent cell-mediated cytotoxicity; ADCP: antibody dependent cellular phagocytosis; AML: acute myeloid leukemia; ALL: acute lymphocytic leukemia; ApoE: apolipoprotein E; AZA: azacitidine; Bcl-2: B-cell lymphoma 2; BiTE: bispecific T-cell engager; BPDCN: blastic plasmacytoid dendritic cell neoplasm; bsAb: bispecific antibody; CAR-T: chimeric antigen receptor T cells; CDC: complement dependent cytotoxicity; CLL-1: C-type lectin-like molecule 1; CR: complete remission; CRi: complete remission with incomplete hematologic recovery; CyTOF: cytometry by time of flight; DART: dual-affinity re-targeting protein; DC: dendritic cell; F(ab): antigen-binding fragment; F(ab’)2: bivalent antigen-binding fragment; Fc: fragment crystallizable; FcγRs: Fc gamma receptors; FcRn: neonatal Fc receptor; FLT-3: fms like tyrosine kinase 3; GO: gemtuzumab ozogamicin; HLE: half-life extended; IgG: immunoglobulin G; IGN: indolinobenzodiazepine pseudodimer; ITAM: immunoreceptor tyrosine-based activation motif; ITIM: immunoreceptor tyrosine-based inhibitory signaling motif; HMAs: hypomethylating agents; HSC: hematopoietic stem cell; HSCT: hematopoietic stem cell transplant; LILR: leukocyte immunoglobulin-like receptor; LSC: leukemic stem cell; M4 AML: myelomonocytic AML; M5 AML: monocytic AML; mAb: monoclonal antibody; MDS: myelodysplastic syndrome; MDSCs: myeloid-derived suppressor cells; MM: multiple myeloma; MRD: minimal residual disease; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; OS: overall survival; PBD: pyrrolobenzodiazepine dimer; PBMC: peripheral blood mononuclear cell; PD-L1: programmed death-ligand 1; PD-1: programmed cell death protein 1; PR: partial response; R/R: relapsed/refractory; scFv: single-chain variable fragment; SHIP-1: Src homology region 2 domain-containing inositol polyphosphate 5-phosphatase 1; SHP-1: Src homology region 2 domain-containing phosphatase-1; SHP-2: Src homology region 2 domain-containing phosphatase-2; Siglecs: sialic acid binding immunoglobulin-like lectins; SIRPα: Signal Regulatory Protein Alpha; TAM: tumor-associated macrophage; TIM-3: Anti-T-cell immunoglobulin and mucin-domain containing molecule-3; TME: tumor microenvironment; Treg: regulatory T cell; TriKE: trispecific killer engager; TNU: treatment-naïve, medically unfit; VH: variable heavy chain; VL: variable light chain.