CD33-targeted Bispecific Antibodies: An Emerging Therapy for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by the clonal expansion of leukemic cells. Despite a better understanding of the biology of AML and the recent approval of new drugs for AML, the 5-year overall survival rate of standard cytotoxic chemotherapy is still only 30%, and new therapies are urgently needed.

In recent years, T-cell-based immunotherapy has received much attention as a promising immunotherapeutic approach for the treatment of various malignancies. AML infected cells are highly sensitive to the cytotoxic effects of functional immune cells, and bispecific T-cell designs provide an effective means of treatment for AML.

CD33 is a sialic acid-binding Ig-like lectin (Siglec) expressed as a 67-kd glycosylated transmembrane protein on normal pluripotent stem-like precursor cells, monopotent stem cells, mature granulocytes, and monocytes. It is also present on macrophages, dendritic cells and can be expressed on B-cell subsets, activated T cells and natural killer cells.

CD33 is expressed on the surface of more than 80% of AML isolates with a high average antigenic density. The differential expression of CD33 on the surface of malignant AML cells makes it an ideal target for immunotherapy. The best-known clinical CD33-targeted immunotherapy is the anti-CD33 antibody gemtuzumab ozogamicin (GO), which was approved in 2000 for the treatment of first relapsed CD33+ AML patients over 60 years of age, but was voluntarily withdrawn from the market due to lack of clinical benefit and increased adverse events. However, GO was reapproved in 2017 after further studies at that time showed benefit from adding GO in fractional doses to standard chemotherapy.

A number of immunotherapies targeting CD33, including ADCs, CAR-T cells and bispecific antibodies, are currently being evaluated in the clinic or are in preclinical development. Four CD33 bispecific antibodies are currently being evaluated in phase I clinical trials.

AMG330 is a short-acting BiTE molecule. Preclinical studies have shown that the anti-CD33 x anti-CD3 structure of the BiTE model is cytotoxic even with a low level of CD33 antigen densities on target cells, making it a candidate for targeting a broad range of CD33+ leukemias, including AML.

AMG673 is a half-life extended BiTE structure that combines the binding specificity of CD33 and CD3, which are fused to the N terminus of a single IgGFc region.

AMV564 is a tetravalent anti-CD33xCD3 TandAb (tandem diabody) structure. Preclinical in vitro and in vivo studies have demonstrated the ability of AMV564 to induce potent cytotoxicity in a dose-dependent manner in CD33+ AML cell lines.

JNJ-67561244 is a fully human IgG4-PAA bispecific antibody that binds the C2 structural domain of CD33 and CD3 to induce T cell recruitment and tumor cytotoxicity. It specifically binds CD33-expressing cells and mediates specific in vitro T cell-dependent cytotoxicity.

With the clinical success of blinatumomab in hematologic oncology, a number of bispecific antibodies targeting the AML-associated antigen CD33 have entered clinical development. To date, the primary serious toxicity of bispecific antibodies targeting CD33 has been cytokine release syndrome (CRS), and mitigation strategies are currently being evaluated. Future trials may well test the combination of bispecific antibodies with other forms of immunotherapy, such as co-stimulation of signaling pathways and targeting of immune evasion mechanisms, to further improve the efficacy and clinical benefit of these treatments.