Y-mAbs Therapeutics presented critical preclinical pharmacokinetics data for its CD38-SADA pretargeted radioimmunotherapy platform at the 2025 American Association of Cancer Research Annual Meeting in Chicago, providing key insights that informed the design of its ongoing first-in-human clinical trial.
Preclinical Pharmacokinetics Reveal Optimal Clearance Profile
The poster presentation, titled "Preclinical and translational pharmacokinetic modeling of the self-assembling and disassembling bispecific fusion protein CD38-SADA for first-in-human pretargeted radioimmunotherapy," characterized plasma concentrations of CD38-SADA in animal models across multiple time points and dose ranges.
The study utilized in vitro binding kinetic parameters and pharmacokinetics data from three mouse studies to characterize the concentration- and time-dependent equilibrium between CD38-SADA tetramers and monomers. A key finding demonstrated that the model's estimated linear clearance of low molecular weight CD38-SADA monomers was 20 times faster than CD38-SADA tetramers.
"Our preclinical models have provided important insights into the circulating levels of CD38-SADA protein in vivo," said Brian Santich, Ph.D., lead author and Vice President of Research at Y-mAbs. "Using these data, we conducted a series of appropriately scaled human PK simulations which informed the design and initial dosing regimen of our first-in-human Phase 1 Trial 1201 in patients with r/r NHL."
Clinical Translation and Trial Design Impact
The differential clearance rates between tetramers and monomers provide crucial evidence supporting the pretargeted radioimmunotherapy approach. Previous preclinical reports showed that non-radiolabeled CD38-SADA tetramers bind with high avidity to tumors during the first "pre-targeting" infusion. The rapid clearance of monomers ensures significantly reduced levels of circulating protein before delivery of the radioactive payload in the second infusion.
This pharmacokinetic profile is particularly important for evaluating tumor-to-normal tissue absorbed dose ratios of Lutetium 177 (Lu 177)-DOTA, the chelated radionuclide administered in Trial 1201. The enhanced clearance differential supports improved therapeutic windows and reduced off-target toxicity.
First-in-Human Trial Advancement
Y-mAbs has already achieved a significant milestone by dosing the first patient in Trial 1201, a Phase 1 study investigating CD38-SADA PRIT with 177Lu-DOTA in adults with relapsed, progressive, or refractory non-Hodgkin lymphoma after at least two prior lines of therapy.
"With the recent dosing of our first patient in Trial 1201, we look forward to reviewing initial patient data as our CD38-SADA program advances," said Norman LaFrance, M.D., co-author and Chief Medical and Development Officer.
Technology Platform and Mechanism
CD38-SADA represents a novel bispecific fusion protein that binds both to the CD38 glycoprotein and to 177Lu-tetraxetan (177Lu-DOTA). The pretargeted radioimmunotherapy approach involves a two-step process: first, non-radiolabeled CD38-SADA tetramers are infused and bind to CD38-expressing lymphoma cells, while unbound protein disassembles into monomers that are rapidly cleared by the kidneys. The second infusion delivers the radioactive payload, which binds directly to CD38-SADA on tumor cells for localized irradiation.
The SADA technology was developed by researchers at Memorial Sloan Kettering Cancer Center, including Dr. Nai-Kong Cheung, and is exclusively licensed to Y-mAbs. Preclinical studies have demonstrated robust anti-tumor efficacy for CD38-SADA PRIT with 177Lu-DOTA.
Therapeutic Target and Market Opportunity
The trial targets CD38-expressing B-cell, T-cell, and natural killer cell lymphomas, representing a significant patient population with limited treatment options after multiple lines of therapy. CD38 is widely expressed on various hematologic malignancies, making it an attractive target for radioimmunotherapy approaches.
Y-mAbs is positioning CD38-SADA as part of its broader radioimmunotherapy portfolio, which includes the FDA-approved DANYELZA (naxitamab-gqgk) for relapsed or refractory high-risk neuroblastoma. The company's SADA platform technology offers potential applications across multiple cancer types and represents a differentiated approach in the competitive radioimmunotherapy landscape.
