Antibody Therapies for Acute Myeloid Leukemia: Unconjugated, Toxin-Conjugated, Radio-Conjugated and Multivalent Formats

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.

Keywords: AML; acute myeloid leukemia; antibody; bi-specific antibody; therapy.

Figure 1

Antibody facilitated T and natural killer (NK) cell cytolysis of leukemia cells. T-cells and NK cells can be redirected to kill acute myeloid leukemia (AML) targets using a variety of antibody formats derived from the natively occurring IgG immunoglobulin molecule. Various approaches are diagrammed with key examples of each antibody format that has been developed. T-cell redirecting antibodies include (A) Bispecific tandem fragment variable format (BiTE, scBsTaFv), of which AMG 330 is an example (CD33 × CD3); (B) Dual Affinity Re-targeting Antibody (DART) (CD123 × CD3); (C) Bispecific single-chain Fv (scFv) immunofusion (Bif) (CD123 × CD3); (D) Bispecific tandem diabodies (TandAb) (AMV-564) (CD33 × CD3); (E) Duobody (CD123 × CD3); (F) Chemically conjugated Fab (CD3 × CD13). NK cell redirecting antibodies include (G) native IgG via antibody-dependent cell-mediated cytotoxicity (ADCC) (e.g., anti-CD123 mAb) CSL362); (H) Bi-specific Killer cell Engager (BiKE) (CD16 × CD33); (I) Tandem triple scfv (sctb); (CD33 × CD33 × CD16); (J) native IgG via reverse-ADCC; antibody directed against a natural cytotoxicity receptor (e.g., anti-NKp30); (K) Chemically conjugated antibodies (CD16 × CD33); (L) Tandem triple scfv (sctb); (CD33 × CD123 × CD16).

Figure 2

Radioimmunotherapy for acute myeloid leukemia. Illustration of (A) a mAb radiolabeled with either a (B) β-particle or (C) α-particle-emitting radionuclide and the track of the particles perfusing the bone marrow to target AML cells. Note that the path length of β-particles is greater than for α-particles leading to β-particle-based RIT used primarily in preparative regimens to myeloablate the bone marrow prior to hematopoietic cell transplantation.