November 29, 2021

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CAR-T and double antibodies based on BCMA target

Success and failure of CAR-T and double antibodies based on BCMA target

 

 

Success and failure of CAR-T and double antibodies based on BCMA target.  On June 24, 2021, AbbVie and Teneobio jointly announced that AbbVie will exercise its exclusive right to acquire TeneoOne, a subsidiary of Teneobio and its main product under development-targeting B cell mature antigen ( BCMA) bispecific antibody therapy TNB-383B.

 

 

For a while, the public’s attention was re-attracted to the ill-fated but infinitely expected CART and dual antibody track for the treatment of multiple myeloma (MM) based on the BCMA target.



The clinical progress of BCMA/CD3 double antibodies

As the second most common hematological malignancy of the blood system after non-Hodgkin’s lymphoma, the recurrence and refractory of multiple myeloma (MM) have always been medical problems. With the successful exploration of cell therapy for hematological tumors, CAR-T therapy based on the BCMA target has gradually increased clinical trials in patients with relapsed or refractory multiple myeloma (r/r MM), and products have been successfully marketed .


Success and failure of CAR-T and double antibodies based on BCMA target


On March 26, 2021, the CAR-T cell therapy product Abecma® jointly developed by Bristol-Myers Bristol-Myers Squibb and Bluebird was officially approved for marketing by the FDA. The indications are that they have received at least three treatments (immunomodulators, proteasome inhibitors and anti-CD38) before treatment. Antibody) in adult patients with relapsed/refractory multiple myeloma (r/r MM). This is the first CAR-T therapy targeting BCMA approved by the FDA for marketing.

 

When CAR-T therapy began to seek a breakthrough in solid tumors, double antibodies based on the BCMA target also began to try to make progress in multiple myeloma. The main double antibody under research is the BCMA/CD3 bispecific antibody. In this field, there are exciting benefits and sighing losses.

 

On June 1, 2021, Johnson & Johnson’s company Janssen announced that the FDA granted the BCMA/CD3 bispecific antibody teclistamab a breakthrough therapy designation (BDT) for the treatment of relapsed or refractory multiple myeloma (r/r MM). This is another good news after teclistamab has obtained the PRIME (Priority Medicine) designation granted by EMA.

 

At the 2021 ASCO conference this year, the results of the Phase 1 study of teclistamab in RRMM patients were also updated (Abstract No. 8007). The efficacy was evaluated according to IMWG standards, with an ORR of 65%; 58% of patients achieved ≥ VGPR, 30% Of patients achieve ≥ CR, and the results are exciting.

 

Unfortunately, Elranatamab (BCMA/CD3 double antibody), a major product under development in the IO2.0 era of Pfizer, has suffered heavy losses. The registered phase II clinical trial of Elranatamab for the treatment of relapsed or refractory multiple myeloma (R/R MM) (NCT04649359) has suspended patient recruitment due to the occurrence of 3 peripheral nerve injury events.

 

Pfizer had high hopes for Elranatamab. In the phase I trial, Elranatamab also showed great potential. At the 62nd ASH Annual Meeting, Pfizer announced the data of the Phase I study (NCT03269136) of Elranatamab in the treatment of relapsed or refractory multiple myeloma (R/R MM). During the dose escalation process, no dose-limiting toxicity was observed at any subcutaneous dose level (80-1000 μg/kg per week).

At the highest dose level, 83% of patients achieved a clinical response. Based on this good data performance, Elranatamab has been granted Fast Track Status (FTD) by the FDA. If the data in Phase II is good, it may be approved for listing. The suspension of patient recruitment at this time will undoubtedly be a huge blow to Pfizer’s expansion in the field of tumor immunity.

 

It can be seen that in the field of RRMM, the progress of BCMA/CD3 bispecific antibodies lags far behind CAR-T, but in terms of mechanism, the target selection of BCM and CD3 is still very reasonable. We will introduce these two in detail next. A target.

 

 

 

BCMA and MM

 


Success and failure of CAR-T and double antibodies based on BCMA target
Figure 1 Effective targets on the surface of MM cells [1]


Choosing to target the BCMA/CD 3 dual target and using multiple myeloma (MM) as the indication is still a relatively safe choice. The above figure shows that BCMA (B cell maturation antigen) is widely present on the surface of MM cells and has become a very popular immunotherapy target for MM and other hematological malignancies in recent years. Currently, there are more than 20 types of immunotherapies developed for BCMA, which are mainly divided into three categories: chimeric antigen receptor T cell therapy, bispecific antibodies, and antibody-drug conjugates (ADC), which can be said to cover the main aspects of current drug development. form.

 

Success and failure of CAR-T and double antibodies based on BCMA target
Figure 2 MM potential immunotherapy targeting BCMA [2]

As mentioned earlier, Abecma has also become the fifth CAR-T product on the market in the world, thus effectively confirming the possibility of a BCMA target drug [3].


And CD3 is the main target of double antibody drug research [4]. The reason why the BCMA/CD 3 double antibody is designed is to bind to the CD3 receptor on T cells while binding to the highly expressed BCMA on the surface of MM cells to recruit CTL to the vicinity of tumor cells to achieve the killing effect. However, whether the CD 3 antigen that is widely expressed in the body will be over-activated and cause an autoimmune response, judging from the data disclosed by many double-antibody products under research, it should be unavoidable.

Success and failure of CAR-T and double antibodies based on BCMA target

Figure 3 Network diagram of double antibody targets under research [4]


Previously, there have been quite a few reports in the literature [5] that for double antibodies that target CD3, if the CD3 antibody end of the double antibody has too strong affinity with the CD3 antigen, it will over-activate the body’s immune T cells and then induce Cytokine release syndrome (CRS), there is a safety risk.


I don’t know if there were 3 peripheral nerve injury events in Pfizer’s Elranatamab clinical phase II trial, whether it is related to the excessive activation of CD3 antigen in the body. I believe that the failure of Elranatamab has also awakened the alarm for other BCMA/CD 3 double antibody products under development. How to minimize adverse immune reactions on the basis of ensuring sufficient effectiveness is the successful development of BCMA/CD 3 double antibodies. The essential.


Figure 4 MM potential immunotherapy targeting BCMA [2]

 

At present, in addition to Johnson & Johnson and Pfizer, there are also many companies that have deployed the dual antibody track in the RRMM field, hoping to make breakthroughs and better benefit clinical patients.

 

(source:internet, reference only)


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