The bispecific antibody teclistamab appears to induce major clinical responses in patients with refractory autoimmune diseases, but with significant safety risks, preliminary evidence from a multicentre case series has shown.
A pair of European-led teams published two papers in the Annals of the Rheumatic Diseases investigating the efficacy and safety of teclistamab across a range of severe autoimmune diseases and for systemic sclerosis specifically.
Teclistamab, a B-cell maturation antigen (BCMA)-directed bispecific antibody already approved in relapsed multiple myeloma, targets plasmablasts, long-lived plasma cells, and their BCMA-expressing memory B-cell pre-cursors, making it an attractive candidate for autoimmune disease treatment, the researchers said.
Autoimmune disease outcomes
An evaluation of teclistamab in 18 patients with autoimmune diseases showed major clinical responses in 61% of patients and minimal-to-moderate responses in 22%, despite discontinuation of immunosuppressive therapy.
The patients (72% women, median age 49) had received a median five prior therapies (rituximab 72%, cyclophosphamide 67%) and were followed for a median five months. They were treated at five centres across Europe.
Their diagnoses included:
- Systemic sclerosis (n =10)
- Idiopathic inflammatory myopathies (n =4)
- Systemic lupus erythematosus (n =2)
- Undifferentiated connective tissue disease (n = 1)
- IgG4-related disease (n =1)
Treatment involved a median cumulative teclistamab dose of 6.36 mg/kg (range, 3.36-8.66 mg/kg) over a median 6 injections during a median 28-day period.
Two patients with severe SSc-associated cardiac involvement died, one due to sudden cardiac death and the other following diffuse alveolar haemorrhage and heart failure, although there was no clear evidence of a causal relationship.
Other adverse events included cytokine release syndrome (CRS, 67%), severe hypogammaglobulinaemia (100%) mostly requiring immunoglobulin replacement, severe infections (67%) and IBD−like colitis (11%).
The researchers said reports of infections and death in patients with advanced cardiac involvement emphasised the need for stringent patient selection, including comprehensive cardiopulmonary assessment and close, longitudinal monitoring.
Refractory systemic sclerosis
A separate analysis focusing on systemic sclerosis suggested teclistamab induced deep tissue depletion of B-cells and plasma cells, and rapid clinical and serological responses in 10 patients (70% female, median age 51).
Researchers found the revised American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) improved from baseline in 5 of the 8 evaluated patients (63%) within 12 weeks, with the remaining 3 patients still demonstrating clinically meaningful improvement.
At last follow-up, 2 of 6 patients assessed with the revised European Scleroderma Trials and Research Group (EUSTAR) activity index reached inactive disease.
B-cells and plasma cells were “almost completely eliminated from bone marrow and skin”, there was a median 70.6% decrease in antitopoisomerase antibody titres, and decreases in serum IgG and vaccination titres, the researchers said.
“Clinically, improvements were observed most pronounced in interstitial lung disease, for which actual reversal of established pathology has rarely been documented,” they wrote.
“Skin involvement, tendon friction rubs, myocardial oedema, and fibrosis measured by LGE and T1 and T2 times on cardiac MRI and digital ulcers also improved rapidly and to an extent unexpected for treatment refractory disease.”
They stressed their sample was small and their findings exploratory.
Professor Susanna Proudman.
Professor Susanna Proudman, director of the rheumatology unit at Royal Adelaide Hospital, said studies of newer therapies had generated much anticipation in the field of rheumatology, but it was still “very early days”.
“Small open label studies of immunotherapy such as CAR-T studies have also demonstrated similar efficacy in terms of B cell depletion and reconstitution, reduction in antibody production and some clinical efficacy depending on the disease. CAR-T studies have shown benefit for SLE but less dramatically so far for systemic sclerosis,” she told the limbic.
“There are many unanswered questions regarding toxicity and longer term outcomes of both CAR-T and bispecific therapies in autoimmune diseases. There will likely be differences depending on the B cell target. For example, cytokine release syndrome and prolonged hypoglobulinaemia seem to be more common after treatment with a BCMA-targeted T-cell engager. Cardiotoxicity has been reported with CAR-T and bispecific T cell engager therapies in the haematological cancer setting.
“In addition to safety [concerns], costs are likely to be significant.”
Professor Proudman said pharmaceutical companies were seeking interest from rheumatologists to be involved in such studies, which was currently the only avenue for patients to access the therapies.
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