BiTEs, DARTS, BiKEs and TriKEs—Are Antibody Based Therapies Changing the Future Treatment of AML?

Abstract

Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody–drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific antibodies have been developed and shown early encouraging results. Bispecific antibodies comprise a wide variety of constructs that share the common concept of simultaneous binding of a surface target on malignant cells and most commonly CD3 on T cells leading to an endogenous, HLA-independent, immune response against malignant cells. However, the use of bispecific antibodies in AML has been limited by the absence of highly specific leukemia-associated antigens leading to on-target, off-leukemia side effects as well as reduced efficacy due to antigen escape. Herein, we discuss the history and evolution of bispecific T cell engagers as well as various adaptations such as dual affinity retargeting antibodies, bi- and tri-specific killer engager antibodies. Common side effects including cytokine release syndrome and management thereof are highlighted. Lastly, we expound on the future direction and integration of such antibody-based therapies with other immunotherapies (programmed cell death-1 inhibitors and chimeric antigen receptor T cells).

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have…”

“…The rate of new cases of AML is 4.3 per 100,000 men and women per year, and the death rate is 2.8 per 100,000 men and women per year. Several targeted medicines, such as FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitor Venetoclax, as well as biotherapeutics (e.g., antibody-drug conjugates) for AML therapy have been developed and approved by the FDA over the last 10 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite these recent advances in therapy, more than 50% of patients who achieve a remission eventually relapse, and the five-year overall survival remains at 29.5%.…”

“…CD123 expression in AML is associated with both higher cell division activity and anti-apoptotic resistance at a cellular level and with a poor prognosis in clinical settings [17,21,22]. Several biotherapeutic agents targeting CD123 have been clinically evaluated against AML, including the CD123-directed recombinant human IL3 fusion toxin Tagraxofusp (SL-401); bispecific antibodies targeting CD123 antigen, such as bispecific T-cell engagers; dual affinity retargeting antibodies; bispecific killer cell engagers; and trispecific killer cell engagers [6,[23][24][25][26][27][28][29][30].…”

Promising New Tools for Targeting p53 Mutant Cancers: Humoral and Cell-Based Immunotherapies

“…The BiTE-mediated interaction of tumor cell with cytotoxic T cell activates proliferation of the latter, thereby increasing the overall number of effector T cells and strengthening the lysis of malignant tumor cells. BiTEs were demonstrated to form such cytolytic synapse with CD8 T cells in a manner independent from MHCI expression on tumor cells ( 51 ).…”

“…Multiple varieties of the BiTE approach were also developed to diversify the landscape of targeted therapies. These include dual affinity retargeting antibodies (DARTs), as well as bi- and tri-specific killer cell engager antibodies (BiKEs and TriKEs) ( 51 ). DARTs use a diabody backbone with the addition of a C-terminal disulfide bridge for improved stabilization.…”