Abstract
In recent decades, therapy for acute myeloid leukemia (AML) has remained relatively unchanged, with chemotherapy regimens primarily consisting of an induction regimen based on a daunorubicin and cytarabine backbone, followed by consolidation chemotherapy. Patients who are relapsed or refractory can be treated with allogeneic hematopoietic stem-cell transplantation with modest benefits to event-free and overall survival. Other modalities of immunotherapy include antibody therapies, which hold considerable promise and can be categorized into unconjugated classical antibodies, multivalent recombinant antibodies (bi-, tri- and quad-specific), toxin-conjugated antibodies and radio-conjugated antibodies. While unconjugated antibodies can facilitate Natural Killer (NK) cell antibody-dependent cell-mediated cytotoxicity (ADCC), bi- and tri-specific antibodies can engage either NK cells or T-cells to redirect cytotoxicity against AML targets in a highly efficient manner, similarly to classic ADCC. Finally, toxin-conjugated and radio-conjugated antibodies can increase the potency of antibody therapies. Several AML tumour-associated antigens are at the forefront of targeted therapy development, which include CD33, CD123, CD13, CLL-1 and CD38 and which may be present on both AML blasts and leukemic stem cells. This review focused on antibody therapies for AML, including pre-clinical studies of these agents and those that are either entering or have been tested in early phase clinical trials. Antibodies for checkpoint inhibition and microenvironment targeting in AML were excluded from this review.
Highlights
The discovery of a means to generate murine monoclonal antibodies by George Köhler and César Milstein garnered the 1984 Nobel Prize in Medicine and paved the way for a new class of therapeutics [1]
While CD45 is not an ideal target, as it is expressed on all hematopoietic cells, it can be used for myeloablative conditioning prior to hematopoietic stem-cell transplantation (HSCT), which is covered in the section on radio-immunotherapy
Investigators at MD Anderson Cancer Center are currently evaluating the efficacy of daratumumab as a stand-alone treatment for R/R acute myeloid leukemia (AML) (NCT 03067571), while Ohio State University is evaluating its effectiveness in combination with donor leukocyte infusions (DLI) for AML patients who have relapsed after allogeneic HSCT (NCT 03537599)
Summary
The discovery of a means to generate murine monoclonal antibodies by George Köhler and César Milstein garnered the 1984 Nobel Prize in Medicine and paved the way for a new class of therapeutics [1]. Acute myeloid leukemia (AML) represents a challenging malignancy to treat, in the situation of relapsed and refractory AML (R/R AML), and antibody therapeutics have not, in general, become a standard of care for most patients. We will discuss basic aspects of AML biology, which inform the strategies that have been used in developing targeted antibody therapies to complement, enhance or replace existing standards of care. We will not cover checkpoint inhibitors that facilitate T-cell anti-tumour responses (e.g., ipilimumab/Yervoy; anti-CTLA-4), or similar approaches to facilitate macrophage anti-tumour responses (i.e., Hu5F9-G4; anti-CD47), or antibodies not directed at cancer cells such as those that target stroma (BMS-936564/MDX1338/ulocuplumab; anti-CXCR4)
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