Johnson & Johnson Unveils Detailed Clinical Data of BCMA/GPRC5D/CD3 Trispecific TCE Antibody JNJ-5322, Demonstrating CAR-T-like Efficacy in Relapsed/Refractory Multiple Myeloma

Jul 09, 2025 15:14 CST Updated 15:14

Johnson & Johnson

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In a previous article, we briefly introduced the clinical data of Johnson & Johnson's BCMA/GPRC5D/CD3 trispecific antibody.InBCMAAndGPRC5D naive In patientsORRAchieved100%, and in patients with triple-drug resistance,ORR Up to86% (≥VGPR：75%), with efficacy comparable toCAR-T. Recently, Johnson & Johnson announced detailed data of this therapy.

In a previous article, we introduced the structure of this molecule, which is an asymmetric 1+1+1 structure. It uses scFv to target BCMA and GPRC5D, while the CD3-binding domain is Fab. The GPRC5D-binding domain is fused to the C-terminus of the antibody and located on the same chain as the BCMA-targeting domain, allowing the antibody to bind both BCMA and GPRC5D without causing steric hindrance with the CD3-binding domain. Compared to bispecific antibodies, JNJ-5322 can bind to three different MM cell types: BCMA-/GPRC5D+.BCMA+/GPRC5D-，BCMA+/GPRC5D+, thereby covering various MM cells, can enhance drug efficacy while preventing drug resistance to a certain extent.

The phase I clinical design of JNJ-5322 is shown in the figure below. During dose escalation, low-dose administration was given as a single dose. For doses above 10mg, a step-up dose (SUD) method was used to reduce CRS reactions. The optimal SUD dose was also explored. Subsequently, based on safety, PK, etc., the SUD was determined to be 5mg. In the dose optimization phase, the target dose reached 50mg.100 or 300mg. The RP2D was finally determined to be 100mg, Q4W, SC.

As of April 15, 2025, a total of 147 patients were enrolled, including 36 patients in the RP2D dose group.Median Age of Patients64Years,Previous median number of treatment lines4Line,100%For the three-drug category exposure,In the P2D dose group, 41.7% of patients were resistant to four drugs, and 25% of patients had previously receivedTargeted therapies for BCMA or GPRC5D, 11.1% of patients have received CAR-T therapy.

In terms of safety, The main hematological toxicity isNeutropenia, lymphopenia, anemia, thrombocytopenia, and leukopenia, of which 30.6% of patients in the RP2D group experienced grade 3/4.Neutropenia, occurring in 41.7% of patientsGrade 3/4Lymphocytopenia, and in terms of non-hematological adverse effects, mainly include infection, taste-related issues, CRS, etc.

In terms of CRS side effects, the 100mg treatment group was divided into two subgroups, one of which received the IL-6R antibody t beforehand.Treatment with ocilizumab. Did not receive t beforehand.In the ocilizumab treatment group, 69.2% of patients experienced CRS reactions, most of which were grade 1, with no occurrence of grade 3 CRS; whereas in the pre-treatment with tIn the ocilizumab treatment group, nearly 20% of patients developed CRS, all of which were grade 1. In terms of neurotoxicity, no ICANS side effects occurred in the RP2D group.

In terms of infection side effects, mainly upper respiratory tract infections, pneumonia, and COVID-19, among which 11.1% of patients in the RP2D group experiencedGrade 3/4 pneumonia.

In terms of GPRC5D-related oral side effectsMainly characterized by dry mouth, dysphagia, glossitis, stomatitis, and decreased appetite. Regarding weight loss caused by taste disturbances, there is an initial decrease in weight during the early stages of treatment, but it gradually recovers afterward.

PK AspectDrug exposure is dose-dependent and stabilizes around 12 weeks, with the antibody's half-life being approximately 17 days. After the first administration, the drug concentration gradually increases and reaches the average maximum concentration on the 7th day.

In terms of efficacy,In the BCMA/GPRC5D exposure group, the overall ORR for the 50-300mg treatment was 55%, with CR and sCR at 30%, and VGPR at 50%. Meanwhile,In the BCMA/GPRC5D naive group, the ORR was 66.7% in the 50mg treatment group, with CR and sCR at 38.1%;In the RP2D treatment group, the ORR was 100%, with CR and sCR at 70.4%, and VGPR or higher at 96.3%; in the 300mg dose group, CR and sCR reached 100%.

InIn the BCMA/GPRC5D naive group, the 12-month PFS for JNJ-5322 treatment was 74.1%, while in the RP2D dose group, the 12-monthThe PFS was 95%, and in this group, all patients except one who discontinued treatment were still receiving treatment as of the cutoff date.

Summary

Based on clinical efficacy and safety, the clinical dosing regimen for JNJ-5322 was determined as follows: SUD of 5mg and target dose of 100mg. In terms of safety, the trivalent antibody has already been approved and marketed.BCMA or GPRC5D bispecific antibodies have better or similar safety. InIn the BCMA/GPRC5D naive group, the ORR was 100%, with 70.4% achieving CR or better.

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