Paper Details

ABSTRACT

Background and Significance:

Immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA) are autoimmune cytopenias characterized by pathogenic autoantibody production, immune-mediated destruction of blood cells, and substantial morbidity. Many patients experience relapsing or refractory disease and remain dependent on chronic therapy. Long-lived plasma cells are increasingly recognized as key drivers of persistent autoantibody production and may contribute to treatment resistance despite conventional B-cell depleting therapies.

Velinotamig (CLN-803, GR1803) is a humanized BCMAxCD3 bispecific T-cell engager designed to redirect T cells toward BCMA-expressing mature B cells and plasma cells. By targeting the plasma-cell compartment, velinotamig may reduce pathogenic autoantibody production and provide a novel therapeutic approach for autoimmune cytopenias. Clinical evaluation of plasma cell-directed immunotherapy in ITP and wAIHA remains limited, highlighting the need for studies investigating this mechanism. Velinotamig has shown convincing clinical activity in patients with relapsed/refractory multiple myeloma, supporting studies in ITP and wAIHA driven by plasma-cell pathogenesis.

Aims:

To evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary clinical activity of administering subcutaneous velinotamig in adults with relapsed/refractory ITP or wAIHA.

Methods:

CLN-803-AIC-101 is a Phase 1b/2a, open-label, multicenter, global study evaluating subcutaneously-administered velinotamig in adults with relapsed/refractory ITP or wAIHA (NCT07738822). The study consists of two parts. Part A is a dose-escalation portion of the study designed to characterize the safety, tolerability, PK, PD, and preliminary effects on disease activity and to identify the dose regimen(s) for further study. Part B is a dose-expansion phase designed to further evaluate safety and clinical activity of selected regimen(s).

Eligible participants are adults aged 18–80 years with relapsed/refractory ITP or wAIHA and an ECOG performance status of 0 to 2. Up to 72 patients may be enrolled across both study parts. Velinotamig is administered subcutaneously over four doses during the first month using step-up dosing strategies. Participants are followed longitudinally for assessment of safety, PK, PD, biomarkers, and disease activity for up to 48 weeks.

The primary objectives in Part A are to evaluate safety and tolerability, and in Part B to further evaluate safety, tolerability, and the effect of velinotamig on disease activity. Primary assessments include incidence and severity of adverse events, serious adverse events, adverse events of special interest, treatment discontinuations, laboratory abnormalities, and protocol-defined hematologic responses.

Secondary and exploratory assessments include PK, immunogenicity, durability and depth of hematologic response, corticosteroid-sparing effects, bleeding outcomes in ITP, hemolysis markers in wAIHA, patient-reported quality of life outcomes, and biomarker analyses evaluating immune-cell populations, plasma-cell depletion, immunoglobulins, autoantibodies, cytokines, vaccine-induced antibodies, and gene-expression profiles.

Discussion:

CLN-803-AIC-101 is designed to evaluate a plasma cell-directed therapeutic strategy for patients with relapsed/refractory ITP and wAIHA. By targeting BCMA-expressing mature B cells and plasma cells through a BCMAxCD3 bispecific T-cell engager, this study investigates a mechanism distinct from conventional B cell-directed therapies and may provide insights into the role of plasma cell depletion in autoimmune cytopenias. The trial will characterize the safety profile, biologic activity, and preliminary clinical efficacy of velinotamig and may help define a novel treatment paradigm for patients with refractory autoantibody-mediated hematologic disease. The study is slated to start in Q4 2026.