What Would Make Therapy Last? How About 2 Targets Each on B Cells and T Cells?

At giant scientific meetings such as the American Society of Hematology Annual Meeting and Exposition, most of the attention flows to the plenary and late-breaking abstract sessions, where presentations typically involve treatments that could reach patients within months.

But the wonder of these gatherings also means finding breakthroughs in the making—the next first-in-class therapy to address an unmet need. At a poster session on December 7, 2025, a team from ModeX Therapeutics Inc presented data on a tetraspecific, a next-generation treatment that simultaneously binds to 4 targets and aims to exceed the staying power of today’s bispecific antibodies and chimeric antigen receptor T-cell therapies, with less toxicity.1

How will they do this? During their poster presentation, the investigators said that current agents for B-cell malignancies “are often limited by target antigen heterogeneity and inadequate efficacy durability.” Their investigational treatment, MDX2003, is described as “a first-in-class tetraspecific T-cell engager-expander,” which reaches 2 targets apiece on both B cells and T cells. They said it targets CD19 and CD20 on B cells “while coengaging CD3 and CD28 on T cells.”1

“This dual targeting strategy is intended to mitigate antigen loss or downmodulation while the CD28 costimulation aims to promote robust T-cell activation, survival, and sustained cytotoxicity,” they wrote. At the same time, the therapy design limits cytokine release (CRS), and the investigators noted that early results point to an improved safety profile.1

Giovanni Abbadessa, MD, PhD | Image: ModeX Therapeutics

In their poster, the investigators presented results of evaluating MDX2003 in preclinical in vitro and in vivo models. The in vitro studies aimed to assess T-cell activation, survival, and production of the cytokines interferon-γ and IL-6. Cell cultures contained lymphoma and leukemia-derived tumor cells, which expressed CD19 and CD20. In vivo antitumor activity was evaluated in a humanized mouse model grafted with B-cell non-Hodgkin lymphoma (NHL).1

Giovanni Abbadessa, MD, PhD, an oncologist and veteran drug development executive who serves as CEO for ModeX Therapeutics, answered questions from The American Journal of Managed Care® (AJMC®) about the abstract and the potential of this multitarget therapy.

AJMC: At first glance, it would seem there is a trade-off between multiple targets and toxicity, but the poster describes a unique mechanism to limit CRS. Can you discuss this in greater detail?

Abbadessa: Directing T cells to malignant B cells via anti-CD19 and anti-CD20 is thought to increase the likelihood of sustained tumor recognition even in the presence of downregulated antigen expression. The costimulation of CD3 and CD28 is aimed to induce efficient antitumor T-cell responses.

We used our proprietary MSTAR platform to select a multispecific configuration that results in a detuned CD3 affinity. In preclinical studies, this led to target tumor cell killing at doses that do not generate high cytokine production. Also, MDX2003 has an Fc-null design that prevents triggering nonspecific immune cell activation through Fc/FcR [Fc receptor] interactions.

Furthermore, 2 T-cell engager molecules that utilize CD3×CD28 costimulation were tested by Sanofi and have...manageable toxicity per several conference presentations.2-4 ModeX’s MDX2001 (CD3×CD28×c-MET×TROP2) and MDX2004 (CD3×CD28×4-1BBL), that also engage CD3 and CD28, are currently being tested in phase 1 studies.5,6

Overall, MDX2003 was designed to have high affinity for the antitumor antigen binders and expected relative low affinity for CD3. However, safety is to be assessed in the clinic, and potential toxicities will be mitigated using step dosing, prophylactic pretreatment, and monitoring.

AJMC: The movement is on to put bispecific (and presumably trispecific) therapies in the community clinic. Could a tetraspecific agent be given at the community level, if not at first?

Abbadessa: MDX2003 is currently administered via intravenous (IV) infusion, which would allow its use in the community clinic setting. Our plan is to develop this molecule for favorable dosing logistics, which will depend on data from the phase 1 trial. Our MSTAR molecules can be formulated for non-IV administration, and this can be addressed as the program progresses.

AJMC: To confirm, this treatment would be for NHL conditions. Is there a particular disease state where it will be tested first?

Abbadessa: We aim to address the unmet needs for patients affected by non-Hodgkin lymphomas. The phase 1 trial is open to most types of B-cell malignancies, except leukemias. The phase 1 trial will be carried out in a range of B-cell non-Hodgkin lymphomas, which usually express CD19 and CD20. These lymphomas include diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphomas, indolent lymphomas, and Waldenström macroglobulinemia. More detailed information, with the inclusion and exclusion criteria, will be available on ClinicalTrial.gov once the study starts. The indication for the phase 2 trial will be dependent on signals seen in phase 1.

AJMC: What are the next steps?

Abbadessa: We aim to launch the first clinical trial for MDX2003 in Q1 [quarter 1] 2026 as a global phase 1 trial in multiple countries. The study, titled MDX-2003-101, will evaluate the safety, tolerability, preliminary antilymphoma efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MDX2003 in participants with B-cell malignancies.

References

1. Wei R, Wu L, Kramer J et al. MDX2003, a novel tetraspecific T-cell engager-expander targeting CD19xCD20xCD3xCD28, demonstrates potent preclinical activity against B-cell malignancies. Presented at: ASH 2025; December 6-9, 2025; Orlando, FL. Paper 3311.
2. Zabaleta A, Blanco L, Kim P, et al. A CD38/CD28xCD3 trispecific T-cell engager (TCE) as a potentially active agent in multiple myeloma patients relapsed and/or refractory (RRMM) to anti-CD38 monoclonal antibodies (mAbs). Blood 2023;142(suppl 1):1921. doi:10.1182/blood-2023-182150
3. Dupuy A, Pelletier L, Giustiniani J, et al. The CD38/CD3xCD28 trispecific antibody (SAR442257) potentially represents a novel therapeutic strategy for peripheral T-cell lymphomas. Blood. 2023;142(suppl 1):4384. doi:10.1182/blood-2023-189088
4. Moreno Garcia V, Oh D-Y, Ryu MH, et al. Phase 1/1b open-label study of an HER2-targeted T-cell engager (TCE)‒SAR443216 in patients (pts) with advanced solid tumors: intravenous (IV) dose-escalation results. Ann Oncol. 2024;35(suppl 2): S518. DOI: 10.1016/j.esmoop.2025.104199
5. Dose escalation and dose expansion study of MDX2001 in patients with advanced solid tumors. ClinicalTrials.gov. Updated June 22, 2025. Accessed December 13, 2025. https://clinicaltrials.gov/study/NCT06239194
6. Dose escalation and dose expansion study of MDX20024 in participants with advanced tumors. ClinicalTrials.gov. Updated November 19, 2025. Accessed December 13, 2025. https://clinicaltrials.gov/study/NCT07110584