CDX-1140

Overview

CDX-1140 (Celldex Therapeutics) is an investigational, fully human agonist monoclonal antibody targeting CD40. It has been evaluated in a first‑in‑human, phase 1 study (CDX1140‑01; NCT03329950) as monotherapy and in combinations (with FLT3L/CDX‑301, pembrolizumab, or chemotherapy). A randomized phase 2 trial in recurrent ovarian cancer is ongoing combining pembrolizumab + bevacizumab with or without CDX‑1140 (NCT05231122). (cdek.pharmacy.purdue.edu)

Mechanism of action

• Target: CD40 on antigen‑presenting cells (dendritic cells, macrophages, B cells) and some tumor cells. CDX‑1140 is an IgG2 agonist that can activate CD40 signaling with minimal Fcγ‑receptor cross‑linking requirements and does not block CD40L, potentially allowing cooperative signaling. Preclinical studies show activation of dendritic and B cells and direct antitumor effects in CD40‑positive lymphoma and certain epithelial models. (aacrjournals.org)

Efficacy

• Monotherapy and CDX‑301 combination (early phase 1 signals): Conference updates reported tumor shrinkage/necrosis signals in head and neck squamous cell carcinoma (HNSCC) and a complete response in one follicular lymphoma patient receiving CDX‑1140 + CDX‑301. These are uncontrolled, early findings. (ir.celldex.com)
• Pembrolizumab combination (anti‑PD‑1/PD‑L1–refractory solid tumors): At SITC 2022, an expansion cohort of the phase 1 trial reported, among 6 evaluable HNSCC patients, 1 ongoing complete response (~16 months at report) and 1 case of stable disease; among 5 evaluable NSCLC patients, 4 had stable disease (up to 13 months). Detailed response rates across the full cohort were not reported. (onclive.com)

No peer‑reviewed, full‑length journal article reporting mature clinical outcomes was identified; available data derive from meeting abstracts, trial listings, and company scientific updates. (aacrjournals.org)

Safety

• Dose finding: In phase 1, the recommended phase 2 dose (RP2D) for systemic dosing was established at 1.5 mg/kg IV. At 3.0 mg/kg, pneumonitis events occurred; most treatment‑related adverse events at or below the RP2D were grade 1–2 with transient liver enzyme elevations. Earlier interim data noted a dose‑limiting pneumonitis at 0.18 mg/kg during escalation; later updates reported generally manageable toxicity at doses up to the RP2D. (ir.celldex.com)
• Combination with pembrolizumab: Described as generally well tolerated in the SITC 2022 expansion cohort report. Specific high‑grade immune‑related events were not detailed in the abstract summary. (onclive.com)

Ongoing/Planned studies

• Phase 1 (completed): CDX1140‑01 (NCT03329950) included monotherapy and combinations (with CDX‑301, pembrolizumab, chemotherapy) to define MTD/RP2D and explore preliminary activity. (cdek.pharmacy.purdue.edu)
• Phase 2 (recruiting): Randomized study in recurrent ovarian cancer testing pembrolizumab + bevacizumab with or without CDX‑1140 (NCT05231122). (cdek.pharmacy.purdue.edu)
• In situ immunomodulation approach: A phase 1 trial (NCT04616248) is testing intratumoral CDX‑301/radiation plus CDX‑1140 and poly‑ICLC; trial-in-progress details were presented at ASCO 2024. (ascopubs.org)

Bottom line

CDX‑1140 is a differentiated CD40 agonist antibody with Fc‑independent agonism and non‑blocking of CD40L. Early clinical signals include a small number of objective responses (e.g., an ongoing CR in refractory HNSCC with pembrolizumab, and a CR in follicular lymphoma with CDX‑301), alongside disease stabilization in some patients. Safety has generally been manageable at the RP2D of 1.5 mg/kg, with pneumonitis emerging at higher doses. Robust, peer‑reviewed efficacy data (response rates, PFS/OS) have not yet been published. (aacrjournals.org)

Further reading

• Mechanism and preclinical activity: AACR Cancer Research abstracts and ASH abstract (CD40 agonism, Fc‑independent activity, direct tumor effects). (aacrjournals.org)
• Phase 1 trial interim results and RP2D: AACR 2019 late‑breaking abstract and company scientific updates. (aacrjournals.org)
• Pembrolizumab combination expansion (SITC 2022): JITC supplement abstract listing and meeting coverage. (synapse.mskcc.org)
• Trials: NCT03329950 (phase 1, completed); NCT05231122 (phase 2, recruiting); NCT04616248 (ASCO 2024 trial‑in‑progress for in situ immunomodulation). (cdek.pharmacy.purdue.edu)

Last updated: Oct 2025