Multiple myeloma treatment: one bridge closer

In this issue of Blood, Konishi et al describe an antibody that stimulates T cells on one side while binding off-the-shelf monoclonal antibodies (mAbs) on the other.¹ 

Bispecific antibodies have injected new momentum into the cancer immunotherapy revolution. By recognizing a surface tumor-specific protein on one arm and stimulating an immune receptor on the other, bispecific antibodies effectively bridge the gap between immune cells and tumor cells. This is especially useful in cancers that elicit a poor immunologic response.

Bispecific antibodies that agonize the T-cell signaling receptor CD3 are particularly promising in hematologic malignancies that invade naturally T cell–rich environments. In multiple myeloma (MM), clonal malignant plasma cells accumulate in the bone marrow, leading to anemia, bone erosion, and end-organ damage from deposition of clonal immunoglobulins. Although MM remains incurable, multiple lines of treatment are now available to patients, significantly extending life expectancy in recent years. Nevertheless, with disease progression, relapses occur at an increased frequency, and treatment needs to be adapted swiftly and sequenced deftly. Two recent phase 2 trials reported striking results of bispecific antibodies stimulating CD3 and recognizing the MM protein BCMA (teclistamab²) or GPC5RD (talquetamab³). In both cases, deep and durable responses were observed in a population of patients with advanced MM, refractory to multiple lines of treatment. Thus, bispecific antibodies represent a promising new frontier in MM treatment.

The currently approved reagents as well as most of those in the pipeline target a single tumor antigen and stimulate a single cell type, mostly T cells. These limitations may expose patients to primary resistance if T cells are hyporesponsive at baseline or acquired resistance if the tumor downregulates the target antigen. Konishi and coauthors, therefore, sought to circumvent these limitations by designing a bridging bispecific T-cell engager (B-BiTE), a reagent coupling an antibody variable fragment specific for the Fc domain of human immunoglobulin G, and an antibody variable fragment that stimulates the CD3 signaling complex. When they incubated this reagent with human mAbs, therefore, they obtained a complex in which the original mAb confers antigen specificity and the B-BiTE activates T cells. Because the arsenal of anticancer drugs includes a growing number of mAbs, the B-BiTE can serve as a backbone to customize T-cell immunotherapy using off-the-shelf antibodies.

The authors demonstrated the efficacy and safety of B-BiTE with a number of in vitro an in vivo approaches. Initially, they generated B-BiTE complexes with the mAbs daratumumab and rituximab, which target CD38 and CD20, respectively. In vitro, in cocultures with target antigen-expressing cell lines, they observed activation of both T cells and, importantly, natural killer (NK) cells. Indeed, the B-BiTE design allows the coupled mAb to still stimulate NK cells through their Fc receptors. The degree of NK stimulation is an important difference between B-BiTE and conventional bispecific antibodies, which are often Fc-silent. Moreover, they showed that T-cell activation also promotes NK proliferation, resulting in a synergistic, powerful dual lymphoid activation.

The authors then showed efficacy of the B-BiTE approach by showing that patient T and NK cells responded to autologous myeloma cells in the presence of daratumumab/B-BiTE. Then they explored the therapeutic advantage conferred by B-BiTEs in mouse models of a CD38^low tumor, as a model of resistance to daratumumab. Here, they showed that sequencing of 2 B-BiTEs complexes using mAbs approved for treatment of MM (daratumumab and elotuzomab, the latter targeting the tumor antigen SLAMF7) is superior to sequencing of the 2 uncoupled mAbs. These experiments were conducted in immune-deficient mice reconstituted with human peripheral blood mononuclear cell (PBMCs) and injected with tumor cells either subcutaneously or, more relevantly, intratibially.

Finally, the authors addressed the essential question of safety. In theory, it is possible that B-BiTEs will uncouple from therapeutic mAbs in vivo and form complexes with existing antibodies, resulting in potentially calamitous and unpredictable toxicity. After injection of human polyclonal immunoglobulin into immune-deficient mice, followed by administration of daratumumab/B-BiTE, the authors collected serum and used it to stimulate human PBMCs. No T-cell or NK-cell reactivity was observed, suggesting that no complex had formed that included an autoantibody specific for antigens expressed by PBMCs. Overall, this work highlights the following advantages of B-BiTEs: they provide 2 binding sites for a tumor antigen of interest, instead of just 1 like mAbs. They simultaneously stimulate T cells and NK cells and the interaction between the 2 cell types. By allowing the rapid generation of new complexes with different mAbs, they can be used for timely treatment changes as soon as resistance develops.

In the future, it will be essential to continue exploring the possibility of in vivo coupling of B-BiTEs with circulating antibodies. This is particularly relevant for patients with autoimmune disease, as well as those with autoantibodies of unknown clinical significance. Moreover, all patients with MM present with elevated amounts of mAbs; although the antigen specificity of these paraproteins remains poorly understood, it has been proposed that chronic antigen stimulation causes monoclonal gammopathy of undetermined significance,⁴ the premalignant, precursor stage of MM. The possibility that these antibodies react to chronic viruses⁵ or self-antigens⁶ should be considered when evaluating the safety of this treatment. Finally, the authors did not observe regulatory T-cell (Treg) activation, despite the ability of Tregs to be activated by CD3. This finding deserves further exploration, especially as preliminary results suggest that Tregs may limit the activity of the bispecific antibody teclistamab in MM.⁷ These concerns notwithstanding, further developments of this therapeutic strategy could provide clinicians with an arsenal of flexible options for T-cell (and NK-cell) redirecting therapy and could benefit the care of patients with MM.

Conflict-of-interest disclosure: The author declares no competing financial interest.