On April 2, 2019 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported interim data from the Company’s CD40 agonist program in a late-breaking poster session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2019 (Press release, Celldex Therapeutics, APR 2, 2019, View Source [SID1234534902]). CD40, expressed on dendritic cells and other antigen presenting cells, is an important target for immunotherapy, as it plays a critical role in the activation of innate and adaptive immune responses.CDX-1140 is a fully human agonist anti-CD40 monoclonal antibody that was specifically designed to balance good systemic exposure and safety with potent biological activity, a profile which differentiates CDX-1140 from other CD40-activating antibodies.

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CDX-1140 is currently in a Phase 1 dose escalation study. The study includes both monotherapy and combination cohorts with CDX-301, Celldex’s dendritic cell growth factor, designed to increase the number of dendritic cells which are critical to initiating antitumor immunity and are a key target for CDX-1140.

"Preclinical data support that CD40 activation could play an extremely important role in cancer immunotherapy by activating anti-tumor immunity and overcoming resistance to PD-1 blockade," said Rachel Sanborn, MD, Co-director of the Thoracic Oncology Program and Leader of the Phase 1 Trials Program at Providence Cancer Institute and a lead investigator in this study. "The interim results presented today have demonstrated that CDX-1140 is a potent activator of CD40 and can be safely administered at doses that we believe will support good tissue and tumor penetration. We are now reaching dose levels that have the potential for meaningful clinical benefit, especially in combination with drugs that target other key immune pathways, and look forward to initiating tumor specific expansion cohorts to test potential clinical activity."

CDX-1140 has a unique combination of properties relative to other CD40 agonist antibodies: potent agonist activity resulting in dendritic cell and B cell activation is independent of Fc receptor interaction, contributing to more consistent, controlled immune activation; CD40 ligand (CD154) binding is not blocked, allowing potential synergy with the natural CD40 activation pathway; and the antibody promotes strong immune activation without significant adverse events in preclinical toxicology studies.

Presentation Highlights:

Abstract #: LB-194: First in human Phase 1 study of the CD40 agonist monoclonal antibody (mAb) CDX-1140 alone and in combination with CDX-301 (rhFLT3L) in patients with advanced cancers: interim results (Sanborn, et. al)

Overview: 30 patients were enrolled in the study at the time of data analysis (n=22 monotherapy; n=8 combination. Six monotherapy dosing cohorts in both solid tumors and non-Hodgkin lymphoma (NHL) (0.01, 0.03, 0.09, 0.18, 0.36 and 0.72 mg/kg) have been completed. The seventh monotherapy cohort at 1.5 mg/kg is currently being enrolled. Two combination cohorts in solid tumors (0.09 and 0.18 mg/kg) with CDX-301 have been completed and the third cohort at 0.36 mg/kg is currently being enrolled. In general, patients have advanced disease and are heavily pretreated (median number of prior therapies: 4 monotherapy arm; 3.5 combination arm).

Safety: CDX-1140 has been generally well tolerated. A maximum tolerated dose (MTD) has not been reached to date and only three patients have experienced serious treatment related adverse events (pneumonitis and hypoxia; possible cytokine release, fatigue and fever; and, fatigue and nausea). High grade, drug-related (Grade 3 and above) changes in liver function tests or platelet count have not been observed to date, including at CDX-1140 dose levels which exceed the MTDs reported with other CD40 agonists. The addition of CDX-301 has not affected the tolerability of CDX-1140 at dose levels tested to date in the combination cohorts.

Systemic Dosing and Biomarker Analysis: Higher dose levels have achieved circulating antibody concentrations in the range of 20 to 30 micrograms CDX-1140 per milliliter. Transient dose-dependent pharmacodynamic effects have been observed including activation of dendritic cells and B cells, along with increases in pro-inflammatory cytokines and chemokines in the blood, all of which are consistent with CD40-mediated immune activation and the hypothesis that CDX-1140 is achieving dose levels optimal for systemic exposure. The addition of CDX-301 has further enhanced cytokine responses.

Early Clinical Activity: While not anticipated at these lower CDX-1140 dose levels, stable disease has been observed in this heavily pretreated population who have received, at a minimum, all standard of care therapies for their tumor type. Recently enrolled dose levels are still under evaluation.

Future development: Additional patient enrollment (backfill) has been initiated at the 0.72 mg/kg CDX-1140 dose level to characterize the effects of CDX-1140 in the tumor microenvironment and tumor specific expansion cohorts are planned. Future combination opportunities are being considered, including with PD-1 or PD-L1 inhibitors, radiation therapy and Celldex’s potent CD27 agonist monoclonal antibody varlilumab. Several B cell lymphomas (subtypes of NHL) express both CD40 and CD27 and varlilumab has been shown to synergize with CDX-1140 in NHL models.