Development of BCMA-based Bispecific ADCs

As a promising and effective cancer therapy strategy, bispecific antibody-drug conjugates (ADCs) have been developed actively in recent years. Several bispecific ADCs have shown significant antitumor activity and a variety of investigated bispecific antibody candidates also received positive preclinical therapy results, which further promote the advance of bispecific ADCs development. Creative Biolabs has extensive antibody development and linker-payload synthesis experience, and now offers clients fast-internalizing receptor BCMA -based bispecific ADCs development services. By using proprietary bio-conjugation technologies, we have demonstrated success in developing a large number of high-quality bispecific ADCs products.

The Overview of BCMA

B-cell maturation antigen (BCMA) is a type III transmembrane protein without a signal-peptide and containing cysteine-rich extracellular domains. BCMA belongs to the family of the tumor necrosis factor receptors (TNFR). It is expressed on multiple myeloma (MM) cell lines. BAFF is a B-cell activating factor act as agonist ligands of BCMA. The addition of BAFF leads to binding to the BCMA receptor identified on normal B-cells resulting in proliferation as well as differentiation and antibody production. APRIL is a proliferation-inducing ligand, which binds to BCMA to induce myeloma cell growth, while several immunosuppressive interactions take place in the bone marrow (BM) microenvironment. Considering the expression of the BCMA receptor on plasma cells along with its important mechanism of action, BCMA could represent an ideal therapeutic target for B-cell malignancies.

Several anti-BCMA therapeutic agents are currently under development, including anti-BCMA monoclonal antibodies (mAbs), or ADCs, and bispecific Abs which bind to BCMA-expressing B/plasma-cells and CD3ԑ- expressing T-cells (BiTEs). The understanding of the exact role of the BCMA and the underlying mechanisms of its regulation and escape will provide valuable help and maximize the exploitation of BCMA targeted therapeutics in clinical practice.

Fig.1 BCMA-based immunotherapies with multiple mechanisms of action against MM cells. (Shih-Feng, 2018)

Antibodies-based Therapeutics Targeting BCMA

The role of BCMA as a potential therapeutic target in the multiple myeloma setting was first evaluated in 2007. The anti-BCMA agent was named cSG1 and it was developed both as a naked Ab as well as with a drug conjugate. This antibody which targeted directly BCMA (cSG1), increased antibody-dependent cell-mediated cytotoxicity (ADCC) by 100-fold. GSK2857916 is a humanized IgG1 anti-BCMA antibody conjugated to the microtubule disrupting agent monomethyl auristatin-F via a stable, protease-resistant maleimidocaproyl linker. This structure is characterized by high stability and high antitumor potency, with low bystander toxicity. GSK2857916 showed robust activity in vitro, inducing ADCC, and leading MM cells to apoptosis.

What Can We Do for You?

BCMA x CD3ԑ bispecific Abs are recently investigated as potential therapies for plasma cell dyscrasias. These agents contain two different domains, one recognizes BCMA on MM cells and the other one binds to the CD3ԑ on T-cells. Binding to the CD3ԑ region leads to T-cell recruitment and activation, resulting in myeloma cell lysis. BI 836909 is the first bispecific antibody with two linked scFvs. In vitro experiments have demonstrated that BI 836909 mediated lysis in MM and plasma cell leukemia cell lines. Additionally, BI 836909 was also evaluated in vivo in xenograft mice models, and the results showed that BI 836909 induced tumor cell depletion in a subcutaneous NCI-H929 xenograft model and prolonged survival in an orthotopic L-363 xenograft model. BI836909 (also known as AMG420) is currently evaluated in an open-label, phase 1 dose-escalation study in RRMM patients.

As a forward-looking custom service provider in ADC development, Creative Biolabs has won a good reputation among our worldwide clients for accomplishing numerous challenging projects. We are willing to provide a series of bispecific ADCs development services to promote your project. We have constructed different epitope combinations for BCMA-based bispecific ADCs development, such as BCMA x CD3, BCMA x CD16, BCMA x CD47, and BCMA x NKp30. If you are interested in our services, please contact us for more details.

Reference

1. Shih-Feng C.; et al. Targeting B cell maturation antigen (BCMA) in multiple myeloma: potential uses of BCMA-Based Immunotherapy. Frontiers in Immunology, 2018, 9: 1821.

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