Context Therapeutics Outlines Post-ADC T-Cell Engager Strategy, Teases Q2 Claudin 6 Data

Context Therapeutics (NASDAQ:CNTX) is focused on developing T-cell engager (TCE) therapies for solid tumors, with an emphasis on addressing resistance that can emerge after antibody-drug conjugate (ADC) treatment, company Chief Executive Officer Martin Lehr said during a fireside chat at Leerink Partners’ global healthcare conference.

Lehr described Context as a research and development company that has acquired all three of its programs externally—two through licenses and one via an acquisition—and said the company does not conduct in-house research. He outlined a strategy built around the growing use of ADCs in earlier lines of therapy across solid tumors and the need for effective options once patients progress on those agents.

Strategy centers on T-cell engagers after ADCs

Lehr said T-cell engagers offer high potency, with cytokine release syndrome (CRS) historically viewed as a key risk. However, he argued clinicians have improved at managing CRS using approaches such as step dosing and steroid prophylaxis, with anti-IL-6 therapies like tocilizumab available as a rescue medication. In his view, the more central development challenge has shifted toward avoiding “on-target, off-tumor” effects and establishing a therapeutic window based on target selectivity.

Context’s pipeline includes three targets:

• Claudin 6 (in the clinic)
• Mesothelin (in the clinic)
• Nectin-4 (expected to enter the clinic imminently)

Lehr said the company expects Phase 1a data from the claudin 6 program in the second quarter of this year and Phase 1a data from the mesothelin program in the middle of the year. The nectin-4 program is “on the doorstep” of clinical testing and could enter the clinic “any day,” he said.

Claudin 6: focus on post-ADC ovarian cancer

Lehr highlighted claudin 6 as an “oncofetal” target he described as truly tumor-selective, which he said may enable higher dosing due to reduced concerns about expression in healthy tissue. He characterized the primary unmet need as treating ADC-resistant disease, particularly in ovarian cancer, where he noted claudin 6 expression is heavily enriched.

In ovarian cancer, Lehr cited the approved ADC mirvetuximab and said multiple topoisomerase (TOPO)-payload ADCs are in development, with “about 10” Phase 3 studies ongoing. He suggested cross-resistance may become a challenge within the ADC class, creating an opening for a different mechanism such as a TCE.

Discussing competition, Lehr referenced other claudin 6 approaches in the market, including CAR-T, ADCs, and TCEs. He noted two other claudin 6 TCE efforts—from Xencor and a private company he identified as Third Arc Bio—and said those programs “detune” CD3. Context, by contrast, uses a high-affinity CD3 design, which Lehr said should maximize T-cell activation and efficacy, with target selectivity expected to support safety.

Dosing interval shift seen as an emerging industry trend

Lehr said the industry is increasingly evaluating less frequent dosing intervals for T-cell engagers to reduce T-cell exhaustion and improve outcomes. He pointed to data he said were presented by Johnson & Johnson on its KLK2 TCE pasritamig, describing improved results with every-three-week dosing compared with weekly dosing, and said every-six-week dosing appeared not inferior to every-three-week dosing. He also said the incidence of CRS in that data set was 8% and that there was not incremental CRS with subsequent doses, attributing early CRS to a small pool of hyperreactive T cells that “burn out” after initial dosing.

Context’s current protocols were not originally designed with extended dosing intervals in mind, Lehr said, and the company is considering protocol amendments to allow every-three-week dosing. He described this as a strategic priority for the year across all programs and said the company expects to disclose more details in the near term.

Claudin 6 update: webinar planned, ovarian enrollment dynamics

Lehr said the upcoming claudin 6 Phase 1a update in Q2 will “almost certainly be a company webinar,” citing the challenges for a small company to coordinate a medical meeting presentation early in its development cycle.

He said the claudin 6 trial was designed to enroll ovarian, endometrial, and testicular cancer patients, but that enrollment in ovarian cancer has been easier than expected. The company is attempting, within protocol constraints, to enrich the study toward ovarian cancer. Lehr also said 80% of the ovarian patients enrolled have been claudin 6-positive, roughly double what the company projected.

For the Q2 update, Lehr said the company aims for “directionally 10” patients with platinum-resistant ovarian cancer who are ADC-exposed at target dose levels. He suggested that a 30% response rate in that group would compare favorably with chemotherapy options such as paclitaxel or doxorubicin, which he described as having 5% to 10% response rates and about a three-month progression-free survival in that setting.

Lehr also shared observations about prior ADC exposure patterns in screened patients. Based on a prospectively screened set of about 100 late-line patients at U.S. academic centers, he said about 80% to 85% were ADC-experienced, mostly with mirvetuximab, with some exposure to Trop-2 agents in trials and occasional combinations involving HER2.

He added that clinicians have been using mirvetuximab more broadly than the label might imply, stating that some physicians treat patients with as little as 1% folate receptor positivity, and that this may expand ADC exposure in the real world. Lehr also said claudin 6 expression appears higher and more homogeneous in later-line ovarian cancer than in earlier samples, sharing examples of H-scores increasing from 100 in platinum-sensitive disease to 300 after patients became platinum-resistant.

On regulatory strategy, Lehr said the company’s “base case” is pursuing full approvals rather than assuming accelerated approval pathways, noting that while mirvetuximab received accelerated approval, newer ADCs with higher response rates moved into Phase 3 trials.

Mesothelin and nectin-4: differentiated designs, new opportunities

For mesothelin, Lehr said Context is currently the only active TCE developer targeting the antigen after other programs were discontinued. He referenced program shutdowns from Zymeworks and Johnson & Johnson due to hypoxia related to mesothelin expression in the lungs. Context’s construct uses a lower-affinity mesothelin binder—Lehr said about 40-fold lower than competitors—and binds to the portion of mesothelin attached to the cell surface, which he said has produced a favorable therapeutic window so far.

Lehr said the company is increasingly interested in pancreatic cancer for the mesothelin program, describing early activity in fifth-line patients and framing longer-term interest in third-line disease. He cited an approximate 5% response rate and two-month progression-free survival for chemotherapy in that setting and said the company has designed the mesothelin protocol to allow more flexibility in enrolling pancreatic cancer patients.

For nectin-4, Lehr emphasized the challenge of targeting an antigen expressed in normal tissues such as skin, and said Context is using a dual masking strategy licensed from BioAtla. He described the antibody as pH-dependent, with about 30-fold lower affinity for nectin-4 in normal physiological pH and reduced ability to bind CD3 and activate T cells in the skin. Lehr said the program completed GLP toxicology testing at up to 200 times the intended therapeutic level before aggregation limited higher dosing, and he called the tox profile “incredibly clean.” He also characterized nectin-4 as one of a small set of targets with clear multi-billion-dollar peak sales potential, while acknowledging it is “exciting and scary” given the safety complexity.

Lehr closed by contrasting TCEs with one-time CAR-T approaches on durability, arguing that redosing and titration give T-cell engagers the ability to sustain responses over time. He said the company hopes to show “line of sight” to durability in upcoming claudin 6 data, despite the limited size and early nature of the dataset.

About Context Therapeutics (NASDAQ:CNTX)

Context Therapeutics (NASDAQ: CNTX) is a clinical-stage biopharmaceutical company focused on the discovery and development of precision therapies for genetically defined patient populations in oncology. The company’s research model centers on identifying novel targets and designing small-molecule and biologic candidates that address key drivers of tumor growth and resistance. Context Therapeutics leverages a biomarker-driven approach to maximize the probability of clinical response, tailoring its development programs to specific molecular subgroups within solid tumors.

With a pipeline advancing through early clinical trials, Context Therapeutics emphasizes strategic collaborations and academic partnerships to accelerate the translation of laboratory findings into patient-focused studies.