BCMA-targeted therapies for MM part I: ADCs and bsAb

Despite the development of many novel therapeutic options for the treatment of multiple myeloma (MM), relapsed/refractory disease still presents a significant challenge. Through exploring effective treatments that target MM cells while limiting off-target toxicity, the discovery of B-cell maturation antigen (BCMA) has led to many new potential therapies.

This type III transmembrane glycoprotein from the tumor necrosis receptor family is highly expressed on malignant and normal plasma cells but is almost undetectable in hematopoietic stem cells and most other non-hematologic tissue.¹ Its ligands are a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF), and downstream effects of their binding with BCMA promote MM proliferation and progression through osteoclast-mediated bone degradation, cell adhesion, and angiogenesis.²

Multiple strategies to develop BCMA-targeted biologic therapies are under investigation, as discussed by Paul et al.² in a recent article published Drugs. In this overview article, we cover the latest clinical data available on antibody-drug conjugates and bispecific antibody classes.

In part II of this series, we present the corresponding clinical data on BCMA-targeted chimeric antigen receptor T-cell therapies.

BCMA antibody-drug conjugates

Antibody-drug conjugates consist of monoclonal antibodies towards a MM cell surface antigen linked to a cytotoxic drug, directly delivering the drug to its target cell. While different targets are being studied, BCMA is currently the most advanced. Table 1 summarizes the current antibody-drug conjugates that targets BCMA.

Table 1. BCMA-targeted antibody-drug conjugates*

Bispecific antibodies

Bispecific antibodies are engineered proteins that bind to an antigen on tumor cells, as well as an antigen on T-cells; thus, redirecting T-cells towards malignant cells.¹ This results in T-cell activation and tumor cell lysis. Bispecific antibodies, also referred to as T-cell engagers, promote sustained T-cell activation, leading to polyclonal expansion of memory T-cells. Several different formats have been created.

• A bispecific T-cell engager consists of two single-chain fragment variables connected by a linker peptide, one for binding the target antigen on the malignant cell and the other for binding the T-cell.
• Bispecific antibodies without an Fc region are smaller and can more easily penetrate tumors; however, they require more frequent or continuous infusion given their short half-lives.
• Bispecific antibodies with Fc domain which create an ‘immunoglobulin G -like’ molecule with Fc-mediated effector functions, have a much longer half-life which allows intermittent dosing and the potential for subcutaneous administration.
• Immunoglobulin G-like tri-specific antibodies are also possible.

Bispecific antibodies are readily available as an ‘off-the-shelf’ product, a significant benefit over chimeric antigen receptor T-cell therapy which involves a lengthy individualized manufacturing process. Early trials have shown promising efficacy, a considerable risk of cytokine release syndrome, and, more rarely, immune effector cell-associated neurotoxicity syndrome. Table 2 summarizes the current BCMA-targeted bispecific antibodies under investigation.

Table 2. BCMA targeted bispecific antibodies*

Conclusion

The development of therapies that target BCMA presents an emerging opportunity to improve the clinical outcomes of patients with relapsed/refractory MM, particularly in the heavily pretreated population. The off-the-shelf accessibility of drugs, such as bispecific antibodies, and the lower overall off-target cytotoxicity observed in initial clinical data is promising for the future management of these patients. BCMA-targeted therapies continue to be evaluated in clinical trials with the aim of closing the unmet clinical need in these heavily pretreated patients and determining the optimal combination and dosing schedules to improve outcomes and quality of life.