Celgene acquired EngMab for $600MM to enrich its programs targeting B-cell maturation antigen (BCMA) for the treatment of multiple myeloma. Celgene is exploiting BCMA in both CAR T (chimeric antigen receptor T-cell) and bispecific antibodies targeting CD-3 (Cluster of differentiation 3), a multimeric protein complex composed of four distinct polypeptide chains (ε, γ, δ, ζ) that assemble and function as three pairs of dimers (εγ, εδ, ζζ). The CD3 complex serves as a T cell co-receptor that associates non-covalently with the T cell receptor (TCR) (Smith-Garvin et al. 2009). The CD3 protein complex is a defining feature of the T cell lineage, therefore anti-CD3 antibodies can be used effectively as T cell markers
What are bispecific antibodies and CAR T-cells?
Bispecific Antibodies (BsAbs) are antibodies that can simultaneously bind two separate and unique antigens (or different epitopes of the same antigen). The primary application of BsAbs have been to redirect cytotoxic immune effector cells for enhanced killing of tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and other cytotoxic mechanisms mediated by the effector cells (Figure 1). Bispecific antibodies are different from normal monoclonal antibodies given the fact that they have dual functionalities. And so BsAbs are in theory superior to conventional mAbs because they offer the benefit of combining two drugs in one molecule.
CAR T-cells are produced via genetic modification of T cells to confer specific tumor antigen recognition, typically through transgenic expression of a high-affinity T-cell receptor or a chimeric antigen receptor (CAR) – Figure 2.
What is BCMA?
BCMA is a member of the TNF-receptor superfamily. This receptor is preferentially expressed in mature B lymphocytes, and may be important for B cell development and autoimmune response (Figures 3 and 4). It has been shown to specifically bind to the tumor necrosis factor (ligand) superfamily, member 13b (TNFSF13B/TALL-1/BAFF), and to lead to NF-kappaB and MAPK8/JNK activation. This receptor also binds to various TRAF family members, and thus may transduce signals for cell survival and proliferation.
BAFF (B-cell Activating Factor) is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptors TNFRSF13B/TACI, TNFRSF17/BCMA, and TNFRSF13C/BAFFR. This cytokine is expressed in B cell lineage cells, and acts as a potent B cell activator. It has been also shown to play an important role in the proliferation and differentiation of B cells. Alternatively spliced transcript variants encoding distinct isoforms have been identified.
BCMA also induces antigen presentation by B-cells.
Is BCMA a suitable target for adoptive immunotherapy strategies?
Carpenter and colleagues investigated this question and found the following:
BCMA had a restricted RNA expression pattern. Except for expression in plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34(+) hematopoietic cells (Figure 5). We detected uniform BCMA cell-surface expression on primary multiple myeloma cells from five of five patients. We designed the first anti-BCMA CARs to be reported and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary multiple myeloma cells.
Who is pursuing BCMA as a target for immunotherapy?
A number of companies are pursuing anti-BCMA approaches – GlaxoSmithKline (GSK) has a BCMA-targeted antibody drug conjugate (ADC) – GSK2857916 and AMGN has a bispecific antibody (AMG420) also in phase I trials. Celgene has a collaboration with bluebird bio on a CAR-T product (bb2121) – a phase 1 trial is ongoing in patients with a diagnosis of MM with relapsed or refractory disease and have had at least 3 different prior lines of therapy including proteasome inhibitor (e.g., bortezomib or carfilzomib) and immunomodulatory therapy (IMiD; e.g., lenalidomide or pomalidomide), or have “double refractory” disease to a proteasome inhibitor and IMiD, defined as progression on or within 60 days of treatment with these agents.
GSK’s ADC, which it obtained from Seattle Genetics, is an antibody that targets BCMA and contains monomethyl auristatin E (MMAE), a cytotoxic compound that targets microtubules and is contained in the approved ADC, Adcetris, for Hodgkin lymphoma.
B-cell maturation antigen (BCMA, also termed TNFRSF17) is an attractive therapeutic target due to its restricted expression on normal and malignant plasma cells (PC). GSK2857916 (or J6M0-MMAF) is a BCMA-specific antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a protease-resistant linker. To evaluate the clinical potential of this agent, tumour cells from seventy multiple myeloma (MM) patients were assessed for BCMA expression by immunohistochemistry and flow cytometry. All patients tested expressed BCMA, at varying levels, and both surface and intracellular expression were observed. BCMA expression is maintained through relapse, extramedullary spread and in residual disease post therapy. BCMA levels may also be prognostically useful as higher levels of BCMA were associated with poorer outcomes, even taking into account genetic risk. We observed rapid internalization of surface BCMA and newly expressed protein by 1 h, suggesting a mechanism for J6M0-MMAF activity even with low surface antigen. J6M0-MMAF mediated cytotoxicity of MM cells varied with dose and antigen levels, with clonogenic progenitors killed at lower doses than mature cells. In comparison, J6M0-MMAF killing of primary CD138+ myeloma cells occurred with slower kinetics. Our observations support BCMA to be a promising therapeutic target in MM for novel therapies such as J6M0-MMAF.