Initiation of Phase 1/2 Trial Marks a Strategic Shift in Targeted B-Cell NHL

In a milestone for the hematologic oncology landscape, the first patient has been dosed in a phase 1/2 clinical trial (NCT07220616) evaluating DS3790, a potential first-in-class antibody-drug conjugate (ADC) targeting CD37 for the treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma. 

The open-label, multicenter study is designed to assess the safety, tolerability, and preliminary efficacy of DS3790 in this patient population, one which continues to face significant challenges with treatment durability and long-term survival.^1,2

Biological Rationale

While CD20 has historically served as the primary target for B-cell malignancies, the clinical community has increasingly sought alternative antigens to overcome resistance mechanisms, such as CD20 downregulation. CD37, a member of the tetraspanin superfamily, has emerged as a compelling candidate.¹

CD37 is heavily glycosylated and prominently expressed across the spectrum of mature B-cell development (from pre-B to mature B-cells) but is notably absent on early progenitor cells and terminally differentiated plasma cells. This expression profile suggests a wide therapeutic window with minimal impact on the hematopoietic stem cell compartment. Furthermore, CD37 plays a functional role in regulating cell survival signaling via the Akt pathway, making its targeting potentially more than just a delivery mechanism, but a direct hit to the tumor’s survival architecture.

Despite its promise, there are currently no FDA-approved CD37-directed therapies, placing DS3790 at the forefront of this niche.

The DXd ADC Platform

DS3790 utilizes DXd ADC technology, which has already demonstrated transformative success in solid tumors, most notably with HER2-targeted agents. The conjugate consists of 3 components:

1. Humanized anti-CD37 IgG1 monoclonal antibody: Specifically engineered for high affinity to the CD37 epitope.
2. Topoisomerase I inhibitor payload (DXd): Anexatecan derivative approximately 10 times more potent than conventional chemotherapy. Its short systemic half-life is intended to minimize off-target toxicities.
3. Tetrapeptide-based cleavable linker: Designed to remain stable in circulation but undergo rapid cleavage by lysosomal enzymes (such as cathepsins) once internalized by the malignant B-cell.

Phase 1/2 Trial Design and Clinical End Points

The global study aims to enroll approximately 420 patients across sites in North America, Europe, and Asia.² The trial is structured in 2 primary phases:

• Dose escalation: Evaluating DS3790 as a monotherapy todetermine the maximum tolerated dose and/or the recommended dose for expansion.
• Dose expansion: Assessing the agent across multiple cohorts of specific B-cell NHL subtypes.

In a move to optimize future standards of care, subsequent cohorts are planned to evaluate DS3790 in combination with other targeted therapies. Key clinical end points include dose-limiting toxicities, objective response rate, duration of response, and progression-free survival.

“The initiation of this trial of DS3790 with its novel CD37 target marks a significant milestone as our first DXd [ADC] in hematology,” said Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, in a news release.¹ “DS3790 expands our portfolio to [7] DXd [ADCs], all developed using our in-house technology, underscoring our dedication to scientific innovation to create new medicines for patients with cancer.”

REFERENCES

1.DS3790 enters clinical development as first DXd ADC in hematology from industry-leading ADC portfolio of Daiichi Sankyo. News release. Daiichi Sankyo. Published and accessed February 4, 2026. https://tinyurl.com/45r6599k

2.A first-in-human trial of DS3790a in participants with hematological malignancies. ClinicalTrials.gov. Updated January 20, 2026. Accessed February 4, 2026. https://clinicaltrials.gov/study/NCT07220616