The BCMA VHH pair behind Carvykti

An elegant example of how VHHs can be engineered into advanced therapies.

Target:

B-cell maturation antigen (BCMA), a cell surface protein highly expressed on malignant plasma cells in multiple myeloma.

Why it matters:

Multiple myeloma is a cancer of antibody-producing plasma cells, and finding selective ways to target these cells remains a major therapeutic challenge. BCMA, a surface protein highly expressed on myeloma cells, has become an important target for new treatments. The development of BCMA-targeting VHHs demonstrates how VHHs (also known as nanobodies) can move beyond conventional biologics to enable innovative therapies such as CAR-T cell therapy.

What makes it special:

Unlike many CAR-T therapies that use a conventional antibody-derived scFv, Carvykti®️ uses two BCMA-binding VHH domains arranged in tandem.

This demonstrates several unique advantages of VHH:

• Compact, modular structure ideal for CAR engineering
• High affinity and specificity for BCMA
• Tandem VHH design enables dual-epitope recognition, increasing binding avidity
• Excellent stability and manufacturability
• Illustrates how VHHs can be used as building blocks, not just standalone therapeutics

Big impact:

• Approved CAR-T therapy for relapsed/refractory multiple myeloma
• Demonstrates the versatility of VHHs in advanced cell therapies
• Highlights the growing role of VHH as engineered therapeutic modules
• Opens opportunities for next-generation CAR-T, CAR-NK and multi-specific immune therapies

Cool fact:

Although Carvykti®️ is often described as a CAR-T therapy, its tumour-recognition domain isn’t a traditional antibody fragment, it’s built from two llama-derived VHH domains that bind different regions of BCMA, showcasing how nanobodies can be engineered into complex therapeutic platforms.

References:
Zhao WH, Liu J, Wang BY, Chen YX, Cao XM, Yang Y, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B-cell maturation antigen in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11:141.

Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed CAR T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314–324.

Martin T, Usmani SZ, Berdeja JG, et al. Ciltacabtagene autoleucel versus standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389:335–347.