NEWS & ANALYSIS Credit: Aaron Bastin/Alamy Stock Photo Aaron Credit: The BCMA bonanza A long and growing list of anti-BCMA candidates — including chimeric antigen receptor-T cell therapies, antibody–drug conjugates and bispecific antibodies — are contending to transform multiple myeloma treatment. Asher Mullard belantamab mafodotin, previously known as University of Pennsylvania. Other historically GSK2857916, by the end of the year. Also out hot targets like PCSK9 for cardiovascular Great targets are scarce, and so researchers in front, Celgene and Bluebird Bio are disease and immune checkpoint PD1/PDL1 across the biopharmaceutical industry anticipating regulatory approval in 2020 for blockers for oncology hold promise for large tend to pile in when they come along. their chimeric antigen receptor (CAR)-T cell populations, but the BCMA activity is all And when the biology is just right, such therapy idecabtagene vicleucel, previously the more impressive for its focus only on targets promise not just new therapeutic known as bb2121. But a long list of other multiple myeloma. options and commercial opportunities, ADCs, bispecifics, CAR-Ts and naked Interest here is driven in part by the but also rare chances to explore emerging monoclonal antibodies are marching to and clinical challenges of multiple myeloma, drug modalities. BCMA, for the treatment through the clinic (Table 1). Indeed, BCMA the second most common haematological of multiple myeloma, is the latest case is the second most popular defined target in malignancy after non-Hodgkin lymphoma. in point. the global cell therapy pipeline, surpassed Despite big advances in recent years with Leaders in this space are set to submit only by CD19. chemotherapy, proteasome inhibitors, first- in-class candidates for regulatory “If you think about all the [CAR-Ts], immunomodulating thalidomide derivatives approval shortly. GlaxoSmithKline ADCs and bispecifics that are going after this and CD38-targeted antibodies, nearly all (GSK) is working to finalize the dossier one target, it’s pretty remarkable,” says Alfred patients still eventually relapse. A dire need for its antibody–drug conjugate (ADC) Garfall, a haematologist at the hospital of the for new drugs remains, and a market exists NATURE REVIEWS | DRUG DISCOVERY VOLUME 18 | JULY 2019 | 481 NEWS & ANALYSIS Table 1 | Select list of anti-BCMA candidates Drug name Sponsor Properties Status CAR- T Idecabtagene vicleucel (bb2121) Celgene/Bluebird Bio CAR- T Phase III, approval anticipated in 2020 JNJ-4528/LCAR-B38M Johnson & Johnson/Nanjing CAR- T Phase II Legend Biotech P- BCMA-101 Poseida Therapeutics CAR- T, with safety switch Phase II, filing anticipated in 2020 bb21217 Celgene/Bluebird Bio CAR-​T,​enriched​for​memory​T cells Phase I JCARH125 Celgene/Juno Therapeutics CAR- T Phase I/II ALLO-715 Allogene Allogeneic CAR-T, with an off switch IND approved Antibody–drug conjugate Belantamab mafodotin (GSK2857916) GlaxoSmithKline Afucosylated antibody conjugated Phase II, filing anticipated to monomethyl auristatin F in 2019 MEDI2228 AstraZeneca Antibody conjugated to Phase I pyrrolobenzodiazepine CC-99712 Celgene/Sutro Biopharma Undisclosed IND approved Bispecific format AMG 420 Amgen BiTE Phase I/II AMG 701 Amgen Half- life extended BiTE Phase I CC-93269 Celgene Bispecific antibody Phase I REGN5458 Regeneron Bispecific antibody Phase I/II JNJ-64007957 Johnson & Johnson Bispecific antibody Phase I PF-06863135 Pfizer Bispecific antibody Phase I Monoclonal antibody SEA- BCMA Seattle Genetics Afucosylated monoclonal antibody Phase I BiTE,​bispecific​T cell​engager​;​CAR-​T,​chimeric​antigen​receptor-​T​cell;​IND,​investigational​new​drug. to support this. Multiple myeloma drugs “When one looks at antibody–drug that bound BCMA and killed cancer cells, achieved sales of nearly US$14 billion conjugates, bispecifics and CAR-Ts, we do but early development work with these in 2017, and are forecast to reach nearly envision a world where all these therapies stalled. For as yet undetermined reasons, $29 billion in sales by 2027. are going to coexist, and that they will have early candidates just didn’t drive sufficiently The BCMA target is also so clean different profiles that will be dependent strong efficacy signals to push the field in its expression profile that it provides on the patient populations and the targets,” forward. And at the same time, the multiple an irresistible testing ground for novel adds Greg Friberg, head of oncology myeloma community was so focused on modalities. “This is a good opportunity development at Amgen, a company that the development of proteasome inhibitors, to really explore different platforms, works on all three modalities. “The reality thalidomide derivatives and CD38 blockers without worrying about the target itself. is we’re going to have to wait and see how that BCMA fell by the wayside, says And hopefully, this will help us to better that plays out.” Yu- Tzu Tai, who studies multiple myeloma examine different targets in the future,” at the Dana–Farber Harvard Cancer says Yusri Elsayed, vice president of BCMA beginnings Center and who has collaborated with haematological malignancies at Janssen, The BCMA gene was identified in 1992, GSK, Amgen, AstraZeneca and Johnson a company that is exploring multiple and was found shortly after to be associated & Johnson on the preclinical validation of BCMA- targeting modalities. with B cell maturation and with multiple BCMA- targeted biologics. myeloma. Further work revealed that BCMA “This is unfortunate because it kind of is only expressed on plasma cells, that it is delayed the development of antibody formats over-expressed on multiple myeloma cells for multiple myeloma, but it is also very If you think about all and that it is dispensable for overall B cell important because clinicians now know how the [CAR- Ts], ADCs and health and homeostasis. These characteristics to use those other drugs,” says Tai. bispecifics that are going make it a compelling target, with a rock The delay created an opening for solid disease association and limited risk of CAR- T developers, mainly in academia after this one target, it’s off-tissue toxicity. initially, who were working on a then- pretty remarkable By 2007 researchers across industry had emergent and now burgeoning modality in identified monoclonal antibodies and ADCs which T cells are extracted from patients and 482 | JULY 2019 | VOLUME 18 www.nature.com/nrd NEWS & ANALYSIS engineered ex vivo to seek out and destroy Given the small sizes of these trials could provide important lessons as to cells expressing antigens of interest. By 2014, and key differences in their designs — how to further lower the risks of systemic as GSK was just starting trials of its ADC, in terms of patient inclusion criteria, inflammatory responses. researchers at the NIH were enrolling patients average prior lines of therapy, whether “A core aim of ours is to learn and improve into a phase I trial of BCMA-targeted CAR- Ts. lymphodepleting chemotherapy was used as we go along, so this is definitely a great CD19-targeted CAR- Ts were inducing and more — the results of the various opportunity for us,” says Elsayed. “We will long- lasting responses in leukaemias and anti- BCMA trials should not be compared learn from this with regard to the CAR-Ts, lymphomas, and haematologists hoped with one another. how to use them in the clinic, how to that this strategy would offer durable “They’re all impressive,” says Garfall, combine them with other drugs, and more.” remissions — if not cures — in multiple who was an investigator on a trial of a myeloma as well. BCMA CAR- T that was partially funded by With initial tweaking of the CAR-T Novartis. This marks an often overlooked technology, researchers started seeing breakthrough, he adds, because one of Autologous cell therapies remarkable responses. In a phase I trial of the big questions for the CAR-T field was have to have exceptionally Celgene and Bluebird’s idecabtagene vicleucel whether it would be possible to make these better efficacy or safety in 33 patients with relapsed or refractory therapies with any target other than CD19. multiple myeloma, who had undergone at “The one big take-home lesson from BCMA profiles to war- rant the cost least 3 prior lines of therapy, 85% of patients is that CAR-T cells will work for other and inconvenience had an objective response with treatment targets,” he adds. and the median time to progression was And yet the durability of the CAR-T 11.8 months. Reporting these results in the responses, even in the patients who Antibody advances New England Journal of Medicine in May, the respond best to these treatments, has not Drug developers are also making a move with study investigators noted that this compared been as high as initially hoped. Patients enhanced antibody formats. favourably with past trials of several salvage are still relapsing at around the 1-year GSK’s ADC belantamab mafodotin, therapies in multiple myeloma, associated mark. “This is a little disappointing,” says the most advanced of these, uses a with response rates of 30% and medians of Garfall. With Novartis’s CD19 CAR-T BCMA- targeted antibody to deliver a 4 months to progression. tisagenlecleucel in relapsed or refractory chemotherapeutic monomethyl auristatin F Celgene and Bluebird now anticipate diffuse large B cell lymphoma, by contrast, warhead directly to cancerous cells. an approval for their CAR-T in 2020, and median duration of response had not been The expression profile of BCMA is so are already working on follow-on CAR- T reached after an average of 19 months clean — restricted to plasma cells and products that they hope will offer better of follow- up, the company reported overexpressed in myeloma — that it is the results yet. “The field of CAR-T cells is last December. perfect candidate for an ADC, adds Hal still in its early adolescence in terms of The biology behind the lack of Barron, CSO at GSK.