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2021 New Antibody drug: Loncastuximab tesirine-lpyl (Zynlonta)

2021 New Antibody drug: Loncastuximab tesirine-lpyl (Zynlonta). On April 23, 2021, the U.S. Food and Drug Administration (FDA) first approved loncastuximab tesirine-lpyl (trade name Zynlonta) for the treatment of relapsed or refractory (r /r) Adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL), DLBCL originating from low-grade lymphoma and high-grade cell lymphoma.

Zynlonta is an antibody-conjugated drug (ADC) that targets CD19. It consists of a humanized anti-human CD19 monoclonal antibody and pyrrolobenzodiazepine (PBD) dimer cytotoxin through a connector. Coupled.

It is worth mentioning that Zynlonta is the first and only CD19-targeted ADC. Previously, Zynlonta received accelerated approval through the priority review process. This accelerated approval is based on positive data from the key LOTIS-2 clinical trial.

The recommended dose of Zynlonta is: 0.15 mg/kg intravenous infusion every 3 weeks for 2 consecutive cycles; thereafter 0.075 mg/kg per cycle every 3 weeks. Zynlonta was developed by the Swiss pharmaceutical company ADC Therapeutics SA. In China, Zynlonta is being developed by Overland ADCT BioPharma, a joint venture established by ADC Therapeutics and Overland Pharmaceuticals.

Pharmacodynamics and pharmacokinetics

The active pharmaceutical ingredient of Zynlonta is loncastuximab tesirine, which is an antibody-conjugated drug targeting CD19. A humanized anti-human CD19 monoclonal antibody dimerizes with pyrrolobenzodiazepine (PBD) through a connector. Somatic cell toxin conjugated.

Once bound to CD19-expressing cells, loncastuximab tesirine will be internalized by the cell, and then release cytotoxin, the toxin can irreversibly bind to DNA, resulting in strong inter-strand cross-links that prevent DNA strand separation, thereby disrupting replication. The process of DNA metabolism eventually leads to cell death. CD19 is a proven popular target for the treatment of B-cell malignancies.

The above table shows the steady-state plasma exposure in the second cycle at the recommended dose approved by Zynlonta. The steady-state Cmax of Zynlonta is 28.2% lower than the Cmax after the first administration, and the time to steady-state is 210 days.

The average volume of distribution (CV%) of Zynlonta is 7.11 L (26.6%). The average clearance rate of Zynlonta decreased over time, from 0.499 liters/day (89.3%) after a single dose to 0.275 liters/day (38.2%) at steady state. In steady state, the average half-life of Zynlonta is 20.8 days.

Clinical Trials

The efficacy of Zynlonta was evaluated in the LOTIS-2 clinical trial (NCT03589469), an open-label one-arm trial that enrolled 145 adult patients with relapsed or refractory diffuse large B-cell lymphoma. These The patient underwent at least 2 systemic treatments.

The patient took Zynlonta 0.15 mg/kg every 3 weeks for 2 consecutive cycles, and then took Zynlonta 0.075 mg/kg every 3 weeks in subsequent cycles until the disease progressed or unacceptable toxicity appeared.

Among the 145 patients enrolled, the median age was 66 years (23-94 years), 59% were male, and 94% of the patients had an ECOG performance of 0-1. Of these patients, 90% are white, 3% are black, and 2% are Asian.

The median of previous treatments was 3 (range 2-7), 63% were refractory diseases, 17% were previous stem cell transplantation, and 9% were previous chimeric antigen receptor (CAR) T cell therapy.

The efficacy endpoint is based on the overall response rate (ORR) assessed by the Independent Review Committee (IRC) using the Lugano 2014 standard. The median follow-up time was 7.3 months (range 0.3 to 20.2), and the median time from initiation of treatment to remission was 1.3 months (range 1.1 to 8.1).

The results showed that the ORR of Zynlonta monotherapy was 48.3% (70/145 cases), the complete response rate (CR) was 24.1% (35/145 cases), and the partial response rate (PR) was 24.1 (35/145 cases). Among 70 patients in remission, the median duration of remission (DOR) was 10.3

(source:internet, reference only)

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