Y-mAbs Therapeutics has announced the administration of both the first protein dose and the 177Lu-DOTA imaging dose to the initial patient in its Phase 1 clinical trial evaluating the company's Self-Assembly and Disassembly (SADA) Pre-targeted Radioimmunotherapy (PRIT) platform. The trial targets patients with relapsed or refractory non-Hodgkin Lymphoma (r/r NHL), representing a significant advancement in the company's radioimmunotherapy development program.
The Phase 1 trial, designated as Trial 1201, is structured as a dose-escalation, open-label, single-arm, multi-center study investigating the safety and tolerability of the CD38-SADA: 177Lu-DOTA Drug Complex. This marks Y-mAbs' second clinical program evaluating the SADA PRIT platform and its first application in hematological malignancies.
Novel Two-Step Approach to Targeted Radioimmunotherapy
The trial employs an innovative two-step approach to deliver targeted radiation therapy. First, the CD38-SADA protein binds with high affinity to lymphoma cells expressing the CD38 glycoprotein. Unbound CD38-SADA protein naturally disassembles into low molecular weight monomers that are cleared by the kidneys, reducing systemic exposure.
In the second step, a radioactive 177Lu-DOTA payload is administered, which selectively binds to the tumor-bound CD38-SADA molecules. This precision targeting aims to deliver localized radiation to cancer cells while minimizing radiation exposure to healthy tissues—a critical advantage over conventional radioimmunotherapy approaches.
"We are excited to announce the dosing of the first patient in Trial 1201 in patients with relapsed or refractory non-Hodgkin Lymphoma, our second clinical program evaluating the SADA PRIT platform and our first in hematological malignancies," said Norman LaFrance, M.D., Chief Development and Medical Officer at Y-mAbs. "Relapsed and refractory NHL presents significant challenges for patients facing limited treatment options and a more aggressive disease course. We believe that our innovative approach to pre-targeted radioimmunotherapy has the potential to significantly improve outcomes in this high-risk population."
Trial Design and Objectives
Part A of the trial focuses on CD38-SADA dose escalation with fixed 177Lu-DOTA payload doses. This phase aims to determine the optimal CD38-SADA protein dose and the ideal interval between the SADA protein administration and the radioactive payload. Primary endpoints include tumor imaging assessment and monitoring for dose-limiting toxicities during the evaluation period.
The trial targets adults with relapsed, progressive, or refractory NHL—including CD38-expressing B-cell, T-cell, and natural killer cell lymphomas—who have received at least two prior lines of therapy (NCT05994157).
Addressing an Unmet Clinical Need
Non-Hodgkin Lymphoma represents a diverse group of blood cancers that originate in lymphocytes. According to recent statistics, NHL accounts for approximately 4% of all cancers in the United States, with relapsed and refractory cases presenting particularly challenging treatment scenarios.
Patients with r/r NHL often face diminishing treatment options and poorer outcomes with each subsequent line of therapy. The CD38-SADA PRIT approach could potentially offer a new treatment modality for these patients by delivering precise radiation therapy to cancer cells while sparing healthy tissues.
The SADA PRIT Platform Technology
The SADA technology was developed by researchers at Memorial Sloan Kettering Cancer Center (MSK), including Dr. Nai-Kong Cheung, and is exclusively licensed to Y-mAbs. The modular design of the platform has enabled the development of multiple bispecific fusion proteins targeting different cancer antigens.
In addition to CD38-SADA, Y-mAbs is advancing GD2-SADA in clinical development for GD2-expressing solid tumors. The versatility of the platform allows for potential applications across various cancer types by changing the targeting moiety while maintaining the same radioactive payload delivery system.
Preclinical Evidence and Future Directions
CD38-SADA PRIT with 177Lu-DOTA has demonstrated robust anti-tumor efficacy in preclinical studies, providing a strong rationale for its clinical investigation. The technology leverages CD38, a glycoprotein highly expressed on multiple myeloma cells and certain lymphomas, as a target for precision therapy.
Y-mAbs' broader pipeline includes DANYELZA® (naxitamab-gqgk), the first FDA-approved treatment for patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow after a partial response, minor response, or stable disease to prior therapy.
As the trial progresses, researchers will evaluate not only safety and tolerability but also preliminary efficacy signals that could inform future development. If successful, the CD38-SADA PRIT approach could represent a significant advancement in the treatment landscape for relapsed or refractory non-Hodgkin Lymphoma and potentially other CD38-expressing malignancies.
