Xencor Reports Initial Plamotamab Phase 1b Data Showing Deep B-Cell Depletion and Preliminary Clinical Improvements in Rheumatoid Arthritis
Xencor, Inc., a clinical-stage biopharmaceutical company developing engineered antibodies for cancer and autoimmune diseases, has announced initial dose-escalation results from its ongoing Phase 1b clinical study of subcutaneous plamotamab in adults with rheumatoid arthritis (RA). The investigational therapy is a bispecific CD20 x CD3 T-cell engager designed to direct T cells toward B cells, which play an important role in several autoimmune conditions.
The initial findings are being presented in a poster session at the American College of Rheumatology (ACR) Convergence 2026 conference in Orlando, Florida. The company reported that treatment with plamotamab produced deep B-cell depletion, accompanied by preliminary improvements in measures of rheumatoid arthritis disease activity. The treatment was also generally well tolerated in the small group of patients evaluated to date.
Alongside the plamotamab update, Xencor provided progress information on its ongoing first-in-human Phase 1 study of XmAb657, another investigational T-cell engager. XmAb657 targets CD19 rather than CD20 and is being evaluated initially in healthy participants, with plans to begin enrolling patients with severe autoimmune diseases in the first quarter of 2027.
The two programs reflect Xencor’s strategy of exploring different B-cell-targeting approaches to address autoimmune diseases. By engaging T cells to eliminate B cells, the company aims to investigate whether these therapies can produce substantial immune-cell depletion and potentially reset aspects of the immune system to achieve sustained disease control.
“Plamotamab and XmAb657 are T-cell engaging XmAb® bispecific antibodies designed to deplete B cells implicated in severe autoimmune diseases, with the potential to reset the immune system and provide sustained disease control for patients,” said Bassil Dahiyat, Ph.D., president and chief executive officer of Xencor.
Dahiyat explained that the company is evaluating two distinct approaches: plamotamab, which targets CD20, and XmAb657, which targets CD19. The objective is to understand how the clinical characteristics of each candidate may address different therapeutic requirements across B-cell-driven autoimmune diseases.
He added that the initial plamotamab results showed deep B-cell depletion and a safety profile considered well tolerated, alongside preliminary improvements in disease activity among adults with moderately to severely active rheumatoid arthritis. For XmAb657, early results in healthy participants have demonstrated reductions in B-cell counts and a safety profile supporting continued dose escalation.
Xencor plans to continue multiple-dose escalation in the plamotamab study while preparing to initiate patient enrollment in the XmAb657 program during the first quarter of 2027.
Initial Phase 1b Results for Plamotamab in Rheumatoid Arthritis
Xencor is evaluating subcutaneous plamotamab in an ongoing Phase 1b study involving adults with rheumatoid arthritis. The trial is designed to determine whether engaging T cells through CD20 targeting can produce clinically meaningful changes in immune activity while maintaining an acceptable safety profile.
The study is enrolling patients whose rheumatoid arthritis has not been adequately controlled with previous systemic treatments. Its primary development objectives include assessing the safety and tolerability of plamotamab, characterizing its effects on B-cell populations, and evaluating preliminary changes in disease activity.
The trial includes single-ascending-dose and multiple-ascending-dose stages. The initial dose levels assessed single administrations, while a later cohort evaluated a two-dose treatment regimen. The multiple-dose portion remains ongoing.
As of the September 21, 2026 data cut, nine patients with active rheumatoid arthritis had enrolled across four dose cohorts. Dose Levels 1 and 2 (DL1 and DL2) each included one patient, while Dose Level 3 (DL3) included three patients and Dose Level 4 (DL4) included four patients.
DL1 through DL3 evaluated single doses of plamotamab. DL4 assessed a two-dose regimen, allowing investigators to examine the effects of repeat administration on B-cell depletion and clinical disease activity.
The enrolled population had longstanding rheumatoid arthritis and substantial disease activity at baseline. The mean duration of disease was approximately 16 years, and all nine participants were receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) when they entered the study.
The mean baseline Clinical Disease Activity Index (CDAI) score was 36.4, reflecting considerable disease activity across the study population. Eight patients had a Disease Activity Score using 28 joints and erythrocyte sedimentation rate (DAS28-ESR) greater than 5.1, placing them in the high disease activity category. One patient had a DAS28-ESR score above 3.2 and at or below 5.1, indicating moderate disease activity.
All enrolled patients tested positive for anti-citrullinated protein antibodies (ACPA), while five patients were positive for rheumatoid factor (RF). These antibody markers are commonly assessed in rheumatoid arthritis and provide additional information about the characteristics of the patient population.
Deep B-Cell Depletion Following Plamotamab Administration
One of the key findings from the initial analysis was the substantial reduction in B-cell levels following treatment with plamotamab. The therapy demonstrated deep B-cell depletion after both single and multiple doses, with reductions in total B cells exceeding 99%.
The company also reported that the duration of B-cell depletion was longer following multiple-dose administration than after a single dose. These findings suggest that repeat dosing may extend the period during which B-cell populations remain suppressed.
Investigators observed an association between the depth and duration of B-cell depletion and reductions in rheumatoid arthritis disease activity. Patients who experienced greater and more sustained B-cell reductions also showed greater improvements in clinical disease measures.
Additional findings from the DL4 cohort showed that memory B cells were rapidly depleted following treatment. These cells remained at low levels through Week 12 and subsequent follow-up, with only limited reconstitution observed during the reported period. This pattern occurred even as total B-cell counts began to recover.
Memory B cells are involved in the persistence and reactivation of immune responses. Their depletion is therefore an important area of interest in the development of B-cell-directed treatments for autoimmune diseases. The observed effects of plamotamab on both total and memory B-cell populations provide information for further investigation of the therapy’s potential biological activity.
Preliminary Improvements in Rheumatoid Arthritis Disease Activity
Alongside the reductions in B-cell populations, Xencor reported preliminary clinical improvements at Week 12 in patients treated at DL3 and DL4. The greatest reductions in disease activity were observed in the multiple-dose DL4 cohort.
The company assessed treatment responses using several established measures of rheumatoid arthritis activity and patient function, including DAS28-ESR, CDAI and the Health Assessment Questionnaire Disability Index (HAQ-DI).
Key findings included:
- DAS28-ESR improvements: At Week 12, the mean change from baseline in DAS28-ESR was -1.2 in DL3 and -3.3 in DL4. These reductions indicated greater improvement in the group receiving the two-dose regimen.
- CDAI reductions: Mean CDAI scores decreased by 15.3 points in DL3 and 25.0 points in DL4 at Week 12. The 25-point reduction in DL4 represented an improvement of more than 50% from baseline.
- Improved physical function: Patients in DL4 experienced an improvement of more than 0.22 points in HAQ-DI at Week 12, indicating a preliminary change in the assessment of physical functioning and disability.
- Joint-count improvements: Reductions in tender and swollen joint counts were observed across all dose cohorts. At Week 12, one patient in DL3 and two patients in DL4 had complete resolution of swollen joints.
The results indicate that the multiple-dose cohort showed larger average improvements across several disease activity measures than the single-dose cohort. However, the findings are based on a small number of patients, and further clinical evaluation will be necessary to determine the consistency, durability and clinical significance of the observed responses.
The company is continuing the multiple-dose escalation phase to gather additional information about the relationship between treatment exposure, B-cell depletion, safety and changes in rheumatoid arthritis activity.
Plamotamab Safety and Tolerability Findings
Xencor reported that plamotamab was generally well tolerated across the single-ascending-dose and multiple-ascending-dose cohorts included in the interim analysis.
One patient in DL4 experienced Grade 1 cytokine release syndrome (CRS), an inflammatory reaction that can occur following treatments designed to activate T cells. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported.
The most frequently reported treatment-emergent adverse events were pyrexia, injection-site erythema and changes in neutrophil counts. Pyrexia was reported in five patients, injection-site erythema in four patients, and decreased or increased neutrophil counts in three patients.
One serious adverse event was reported in a patient enrolled in DL4 who had a medical history of nephrolithiasis. The patient experienced nephrolithiasis complicated by pyelonephritis. Investigators considered the event unrelated to plamotamab, and the patient discontinued study treatment.
The safety observations will continue to be assessed as additional patients receive treatment and the study advances through dose escalation. Monitoring for CRS, neurological events, injection-site reactions and other adverse events remains important as investigators evaluate the appropriate dosing approach for the therapy.
XmAb657 Phase 1 Study Shows Early B-Cell Reductions
In addition to the plamotamab findings, Xencor provided an update on XmAb657, an investigational bispecific CD19 x CD3 T-cell engager being developed for severe autoimmune diseases.
Like plamotamab, XmAb657 is designed to engage T cells and direct them toward B cells. However, it targets CD19 rather than CD20, providing a distinct approach to B-cell depletion. By investigating both targets, Xencor aims to understand whether differences in B-cell targeting may translate into different clinical profiles or therapeutic opportunities across autoimmune conditions.
The company is conducting a first-in-human, open-label Phase 1 dose-escalation study of subcutaneous XmAb657. The trial initially involves healthy participants and is designed to evaluate safety, tolerability, pharmacological activity and the effects of treatment on B-cell populations.
The planned clinical development program also includes patients with idiopathic inflammatory myopathies, systemic sclerosis and Sjögren’s disease. These conditions represent serious autoimmune disorders in which B cells can contribute to abnormal immune activity and disease progression.
As of November 1, 2026, 30 healthy participants had enrolled across five single-ascending-dose cohorts.
Early results showed dose-dependent reductions in B-cell counts following XmAb657 administration. In the fifth cohort, which represented the highest single-dose level evaluated to date, all participants experienced reductions in B-cell counts from baseline by Day 2.
The median maximum reduction in B-cell counts in Cohort 5 was 86% from baseline. These findings provide early evidence of the candidate’s biological activity and support continued investigation through the planned dose-escalation program.
XmAb657 Safety Findings and Planned Clinical Development
The company also reported preliminary safety observations from the healthy-participant portion of the XmAb657 study.
One participant in Cohort 5 experienced Grade 1 CRS. No cases of ICANS had been observed as of the reported data cut.
Injection-site reactions were the most commonly reported adverse events. Grade 1 injection-site reactions occurred in six participants, while Grade 2 reactions were reported in nine participants.
Xencor stated that the safety findings support further dose escalation. The company expects to complete one additional single-dose cohort in healthy participants by the end of 2026.
In the first quarter of 2027, Xencor plans to begin enrolling patients with severe autoimmune diseases into multiple-ascending-dose cohorts. The planned patient populations include individuals with idiopathic inflammatory myopathies, Sjögren’s disease and systemic sclerosis.
The transition from healthy-participant dose escalation to patient studies will allow the company to investigate XmAb657 in populations with the autoimmune conditions it is intended to treat. Further evaluation will help establish the candidate’s safety profile, dosing characteristics and potential effects on disease-related immune activity.
Xencor Advances Two B-Cell-Targeting Approaches for Autoimmune Diseases
The clinical programs for plamotamab and XmAb657 represent two complementary approaches within Xencor’s broader strategy to develop engineered antibodies for autoimmune diseases.
Plamotamab targets CD20 and has produced greater than 99% reductions in total B-cell counts in the initial rheumatoid arthritis study. Its early clinical findings also include improvements in disease activity measures, particularly in the two-dose cohort. XmAb657 targets CD19 and has demonstrated dose-dependent B-cell reductions in healthy participants, including a median maximum reduction of 86% in the highest single-dose cohort evaluated to date.
Both programs use T-cell engagement to target B-cell populations, but their different molecular targets may provide distinct opportunities for addressing autoimmune conditions. Xencor is continuing to assess how the depth and duration of B-cell depletion relate to clinical outcomes, treatment tolerability and the potential for sustained disease control.
The findings presented at ACR Convergence 2026 are preliminary and come from early-stage studies with limited participant numbers. Larger and longer-term clinical studies will be needed to establish the safety, efficacy, optimal dosing and durability of treatment effects for both candidates.
Xencor plans to continue multiple-dose escalation with plamotamab while advancing XmAb657 toward patient enrollment in early 2027. These next steps are expected to provide additional information about the potential role of CD20- and CD19-directed T-cell engagers in the treatment of severe autoimmune diseases.
The plamotamab poster, titled “Phase 1 Study of Plamotamab, a Bispecific CD20xCD3 T-cell Engager, in Adult Patients With Rheumatoid Arthritis: Interim Results,” will be available through the Publications page of Xencor’s website at Xencor and under the Events & Presentations section for investors.
About Plamotamab
Plamotamab is an investigational CD20 x CD3 bispecific T-cell engager designed to redirect T cells to target and deplete CD20-expressing B cells. In a prior Phase 1 study in patients with B-cell malignancies, plamotamab demonstrated preliminary antitumor activity and deep depletion of circulating B cells. Xencor believes these findings, together with the established role of B cells in certain autoimmune diseases, support its evaluation in autoimmune diseases.
Xencor is conducting a Phase 1b, open-label, dose-escalation study of subcutaneously administered plamotamab in patients with moderately to severely active rheumatoid arthritis whose disease has not been adequately controlled with prior therapies. The study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of plamotamab.
About XmAb657
XmAb657 is an investigational CD19 x CD3 bispecific T-cell engager designed to redirect T cells to target and deplete CD19-expressing B cells. XmAb657 incorporates Xencor’s XmAb® 2+1 bispecific antibody format and Xtend™ Fc technology and is designed to provide potent B-cell depletion and an extended circulating half-life. In non-human primate studies, a single dose of XmAb657 reduced B cells by greater than 99.98% in peripheral blood, bone marrow and lymph nodes, with depletion sustained for at least 42 days.
Xencor believes these findings support its evaluation for the treatment of autoimmune diseases in which B cells contribute to disease pathogenesis. Xencor is conducting a first-in-human, Phase 1, open-label, dose-escalation study of subcutaneously administered XmAb657 in healthy participants and patients with idiopathic inflammatory myopathies, systemic sclerosis and Sjögren’s disease. The study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of XmAb657.
About Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by joint inflammation that causes pain, swelling and stiffness and can lead to progressive joint damage and disability. The disease can also affect other organs and tissues, including the lungs, heart and eyes, further impairing health and quality of life. B-cell dysfunction and disease-associated autoantibodies contribute to RA pathogenesis, supporting the rationale for investigating B-cell-directed therapies.
Although disease-modifying antirheumatic drugs are available, including conventional therapies, biologic agents and targeted small molecules, some patients have inadequate responses or lose response over time. There remains a significant need for additional therapies that provide sustained disease control and improve long-term outcomes, particularly for patients whose disease remains active despite available treatments.
About Idiopathic Inflammatory Myopathy
Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases, including dermatomyositis and polymyositis, in which immune-mediated injury can cause muscle weakness and disability. Depending on the subtype, patients may also experience skin involvement, difficulty swallowing and interstitial lung disease, contributing to substantial morbidity.
B cells and disease-associated autoantibodies are implicated in the underlying disease mechanisms of several IIM subtypes, providing a rationale for investigating B-cell-directed therapies. Current treatment commonly includes corticosteroids and other immunomodulatory or immunosuppressive therapies, but some patients experience persistent disease activity or treatment-related complications. There remains a need for additional therapies that provide sustained disease control and improve long-term patient outcomes.
About Sjögren’s Disease
Sjögren’s disease is a chronic, systemic autoimmune disorder characterized by inflammation and dysfunction of moisture-producing glands, commonly resulting in dry eyes and dry mouth. Patients may also experience debilitating fatigue, joint pain, and systemic manifestations affecting the lungs, kidneys, nervous system and other organs. Abnormal B-cell activity, including the production of autoantibodies, is an important feature of the disease and contributes to its underlying immune dysfunction.
There are currently no FDA-approved therapies that address the underlying autoimmune causes of Sjögren’s disease. Current management focuses on relieving symptoms and treating systemic manifestations, which may require immunomodulatory or immunosuppressive medications. Despite available treatments, a substantial unmet need remains for therapies that provide sustained control of disease activity.
About Systemic Sclerosis
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by immune system dysfunction, abnormalities of small blood vessels and excessive accumulation of scar tissue, or fibrosis, in the skin and internal organs. Patients may experience skin thickening, joint pain and impaired circulation, as well as serious complications involving the lungs, heart, gastrointestinal tract, and kidneys. These complications can lead to progressive organ damage, substantial disability and reduced survival.
B-cell dysfunction is implicated in disease pathogenesis, and disease-associated autoantibodies are a hallmark of SSc, providing a rationale for investigating B-cell-directed therapies. Current treatment strategies are tailored to specific disease manifestations and include immunomodulatory, immunosuppressive, antifibrotic, and vascular therapies. Despite available treatments, there remains a significant need for additional therapies that provide sustained disease control and prevent organ damage.
About Xencor
Xencor is a clinical-stage biopharmaceutical company developing engineered antibodies for the treatment of patients with cancer and autoimmune diseases. More than 20 candidates engineered with Xencor’s XmAb® technology are in clinical development, and multiple XmAb medicines are marketed by partners. Xencor’s XmAb engineering technology enables small changes to a protein’s structure that result in new mechanisms of therapeutic action.