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*

ADC, antibody-drug conjugate; AE, adverse event; BCMA, B-cell maturation antigen; CR, complete response; DOR, duration of response; IgG, immunoglobulin G; MMAF, monomethyl auristatin-F; mRNA, messenger RNA; ORR, overall response rate; PFS, progression-free survival; TEAE, treatment-emergent adverse event; U.S. FDA, United States Food and Drug Administration. *Adapted from Paul, et al.2
Antibody-drug conjugate	Drug information	Latest clinical trial data
Belantamab mafodotin	Humanized IgG1 monoclonal engineered antibody that is afucosylated and bound to a microtubule inhibitor MMAF through a protease-resistant maleimidocaproyl linker. Additional information: Belanatamab mafodotin had its U.S. marketing authorization withdrawn based on the results from DREAMM-3.	DREAMM-3 (NCT04162210) ORR: 41.0% Median DOR: not reached Median PFS: 11.2 months Serious AEs: 43.0% Fatal AEs: 7.0%3
CC‐99712	This agent contains a maytansinoid toxic payload that forms part of the microtubular polymerization inhibitors and is attached to a non-cleavable linker. Additional information: Orphan drug designation granted by the U.S. FDA.	(NCT04036461) Trial ongoing – interim data unavailable
HDP‐101	Novel amanitin derivative as its payload, which inhibits formation of mRNA in the targeted cell, a unique mechanism that works independently of mitotic cell division, making it effective in less proliferative, more dormant clones. Additional information: Patients whose myeloma cells harbor 17p deletion may have a specific therapeutic sensitivity towards HDP-101.	(NCT04879043) Currently recruiting – data unavailable

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*

Ab, antibody; AE, adverse event; BCMA, B-cell maturation antigen; CHMP, Committee for Medicinal Products for Human Use; CR, complete response; CRS, cytokine release syndrome; DOR, duration of response; EMA, European Medicines Agency; ICANS, immune effector cell-associated neurotoxicity syndrome; IgG, immunoglobin G; IV, intravenous; mAb, monoclonal Ab; MMAF, monomethyl auristatin-F; MRD, measurable residual disease; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokineitc; RRMM, relapse/refractory multiple myeloma; SAE, serious adverse event; sCR, stringent complete response; SC, subcutaneous; TEAE, treatment-emergent adverse event; VGPR, very good partial response. *Adapted from Paul, et al.2
Bispecific Ab	Drug information	Latest clinical trial data
ABBV-38 (Tnb-383B)	Fully human triple-chain IgG4 Ab with two anti-BCMA domains to favor cell surface binding. Additional information: Beneficial PKs allow dosing every 3 weeks.	(NCT03933735)4 ORR: 56% ≥VGPR: 42% CRS: 60% Grade≥3 TEAE: 59% SAE: 18%
Alnuctamab (CC-93269)	Asymmetric bivalent IgG compound that binds to CD3 (monovalently) and BCMA (bivalently). Additional information: Initially IV, study pivoted to SC administration to improve tolerability. High rates of CRS reported (77%), so prophylactic dexamethasone implemented for higher doses.	(NCT03486067) 5 IV/SC ORR: 39%/53% IV/SC CRS: 76%/56% IV PFS: 36.5 months in responders SC MRD negativity: 80%
Elranatamab	Humanized mAb that targets BCMA and CD3 like other agents but is paired to an IgG2a Fc backbone using hinge mutation technology Additional information: Ten patients in the phase I MagnetisMM-1 study had previous treatment with BCMA-targeted therapy and showed a response rate of 70%, suggesting activity in this population.	MagnetisMM-16 (NCT03269136) ORR: 64% CR/sCR rate: 38%. Median DOR: 17.1 months Median PFS: 11.8 months MRD negativity, at any point: 100% MRD negativity at >6 months: 62%   MagnetisMM-37 (NCT04649359) ORR: 61% 9-month DOR rate: 84.4% 14.7 month median follow-up: median PFS and OS not reached. CRS: 57.7%
Linvoseltamab (REGN5458)	Fully humanized  bispecific Ab with an Fc region and Fab arms that bind to CD3 and BCMA.	LINKER-MM18 (NCT03761108) 200 mg recommended dose ORR: 71% ≥CR: 30% Response at ≥6 months: 84% Median PFS: not reached ICANS: 5.9% CRS: 45.3%
REGN5459	Bispecific Ab targeting CD3 and BCMA but with different binding characteristics compared to REGN5458.	(NCT04083534) 9 ORR: 65.1% ORR (480/900 mg): 90.5% ≥CR (480/900 mg): 61.9% CRS: 53.5% Infections: 62.8%
Teclistamab (JNJ-64007957)	IgG4-engineered antibody targeting CD3 and BCMA. Additional information: Combination therapy with daratumumab +/- pomalidomide under investigation. In August, 2022, teclistamab was granted conditional marketing authorization from the European Commission as monotherapy for adult patients with RRMM. In July 2023, the EMA CHMP recommend a new reduced dosing schedue for teclistamab, involving biweekly dosing of 1.5 mg/kg in patients who have achieved a CR for ≥6 months.	MajesTEC-110 (NCT03145181) Median OS: 18.3 months Median PFS: 11.3 months   MajesTEC-210 (NCT04722146) ORR: 74.1% DOR ≥12mo: 87.2% ≥CR: 51.9% CRS: 75%

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.