On April 27, 2016 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company developing checkpoint antibodies and cancer vaccines, reported that the first patient has been dosed in the company’s Phase 1 clinical trial of AGEN1884, an anti-CTLA-4 checkpoint (CPM) antibody (Press release, Agenus, APR 27, 2016, View Source [SID:1234511496]).

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The open-label, multicenter trial in patients with advanced or refractory cancer is designed to evaluate the safety of AGEN1884 and determine the estimated maximum tolerated dose.

"Advancing AGEN1884 into the clinic is an important milestone for Agenus," said Garo Armen, PhD, Chairman and CEO of Agenus. "Since the acquisition of 4-Antibody two years ago, we have completed additional strategic acquisitions and formed new collaborations considerably strengthening our antibody research and development capabilities."

AGEN1884 is an anti-CTLA-4 (cytotoxic T-lymphocyte antigen-4) checkpoint antibody that enables the immune system to find and destroy cancer cells. It is the first of a series of CPMs, discovered using Agenus’ proprietary platform, to enter clinical development. Anti-CTLA-4 antibodies have been highly efficacious in treating cancer and curative in some patients for whom standard of care has proven unsuccessful. Recent clinical data also suggests that anti-CTLA-4 antibodies are emerging as a central component of combination immunotherapeutic regimens for fighting cancer.

Agenus has in-house technologies for rapid discovery and development of CPMs using its integrated mammalian, yeast and phage display platforms. The company also possesses the capability to generate optimal cell lines and manufacture GMP grade antibodies and vaccines.

"We expect additional checkpoint antibodies from our portfolio to commence clinical trials during the course of this year. We believe our CPMs, vaccines and adjuvants will provide advantages in advancing the fight against cancers. This effort will be particularly enhanced by our ability to combine these agents as required," said Robert B. Stein, MD, PhD, Agenus’ President, Research & Development.

This Phase 1 clinical trial is taking place at leading centers in the United States, including The Ohio State University Comprehensive Cancer Center and the Comprehensive Cancer Center of Northwestern University. AGEN1884 was developed under a Collaborative Research and Development Agreement between Ludwig Cancer Research, 4-Antibody AG and Recepta Biopharma S.A.

About Checkpoint Antibodies

Promising clinical data from trials employing monoclonal antibodies that bind to checkpoint molecules, such as CTLA-4 and programmed death receptor-1 (PD-1), have generated considerable excitement in the field of cancer immunotherapy. These molecules serve as checks employed by the body to prevent a runaway immune response, which can be debilitating and even deadly. Unfortunately, these necessary mechanisms of control can hinder the anti-cancer immune response. They can be harnessed by cancer cells as a defense against immune attack. Agenus is developing a broad pipeline of antibodies that bind to key checkpoint proteins and activate or block their activities for use in cancer therapy.

On April 27, 2016 Celldex Therapeutics, Inc. (Nasdaq:CLDX) reported that it has initiated an open-label Phase 1/2 safety and tolerability study of glembatumumab vedotin in patients with unresectable stage IIIB or IV, gpNMB-expressing, advanced or metastatic squamous cell carcinoma (SCC) of the lung, who have progressed on prior platinum-based chemotherapy (Press release, Celldex Therapeutics, APR 27, 2016, View Source [SID:1234511479]).

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Glembatumumab vedotin is a fully human monoclonal antibody-drug conjugate (ADC) that targets gpNMB, a protein overexpressed by multiple tumor types, including SCC of the lung, where approximately 85 percent of patients overexpress the marker. Overexpression of gpNMB has been shown to promote the invasion and metastasis of cancer and has been associated with poor clinical outcome. Celldex has entered into a collaborative relationship with PrECOG, LLC, which represents a research network established by the Eastern Cooperative Oncology Group (ECOG), and PrECOG, LLC will conduct the study.

"While checkpoint inhibitor therapy has been an important development for patients with squamous cell lung cancer, the majority of patients still require new, effective treatment options—especially targeted therapies," said Thomas Davis, M.D., Executive Vice President and Chief Medical Officer of Celldex Therapeutics. "gpNMB, the target of glembatumumab vedotin, is strongly expressed in the vast majority of squamous cell lung cancers. Glembatumumab vedotin has consistently induced notable response rates in other difficult to treat cancers that overexpress gpNMB. We hope to elicit similar activity in squamous cell carcinoma and look forward to completing this study."

Glembatumumab vedotin is currently being evaluated in patients with metastatic triple negative breast cancers that overexpress gpNMB in the registrational METRIC study, as well as in a Phase 2 study in patients with advanced melanoma who have progressed after at least one checkpoint inhibitor therapy and, if applicable, BRAF- or MEK-targeted therapy. It has been previously evaluated in a Phase 2 study in advanced breast cancer (the EMERGE study), a Phase 1/2 study in advanced breast cancer and a Phase 1/2 study in patients with unresectable stage III or IV melanoma. Also, Celldex and the National Cancer Institute (NCI) have entered into a Cooperative Research and Development Agreement (CRADA) under which the NCI is sponsoring two studies of glembatumumab vedotin—one in uveal melanoma and one in pediatric osteosarcoma. Both studies are currently open to enrollment.

Study Design
This Phase 1/2 study will enroll patients with gpNMB-positive stage IIIB or IV non-small cell lung cancer (NSCLC) of squamous histology who have previously been treated with platinum-based chemotherapy. gpNMB positivity will be determined by a greater than, or equal to, five percent gpNMB expression in tumor epithelial cells. Glembatumumab vedotin will be administered once every three weeks until disease progression or intolerance. The study is expected to include 10 sites in the United States.

The study will include a dose-escalation phase followed by a two-stage Phase 2 portion (Simon two-stage design). The Phase 1, dose-escalation portion of the study will assess the safety and tolerability of glembatumumab vedotin at the current dose of 1.9 mg/kg and then 2.2 mg/kg in order to determine whether higher dosing is feasible in this population. The first stage of the Phase 2 portion will enroll approximately 20 patients, and if at least two patients achieve a partial response or complete response, a second stage may enroll an additional 15 patients. The primary objective of the Phase 2 portion of the study is to assess the anti-tumor efficacy of glembatumumab vedotin in squamous cell lung cancer as measured by objective response rate (ORR). Secondary objectives of the study include analyses of safety and tolerability and further assessment of anti-tumor activity across a broad range of endpoints.

About Squamous Cell Lung Cancer
Lung cancer is the leading cause of cancer related deaths in the world, with an estimated one million new cases worldwide and around 216,000 in the U.S. annually. Non-small cell lung cancer (NSCLC) represents more than 80 percent of all lung cancers, and squamous cell carcinoma (SCC) of the lung accounts for approximately 30 to 40 percent of NSCLC. While new treatment options, especially targeted therapies, have become available for patients with adenocarcinoma, another type of NSCLC, clinical studies have not identified targeted therapies with major benefits for patients with SCC of the lung. Recent improvements for patients with SCC of the lung include checkpoint immunotherapy; however, not all patients respond to this treatment, and new therapeutic options are needed. Approximately 85 percent of patients with SCC of the lung have tumors that overexpress gpNMB, the target of glembatumumab vedotin.

About Glembatumumab Vedotin
Glembatumumab vedotin (CDX-011) is a fully human monoclonal antibody-drug conjugate (ADC) that targets glycoprotein NMB (gpNMB). gpNMB is a protein overexpressed by multiple tumor types, including breast cancer, melanoma, lung cancer, head and neck cancer, uveal melanoma, osteosarcoma, pancreatic cancer and glioblastoma. gpNMB has been shown to be associated with the ability of the cancer cell to invade and metastasize and to correlate with reduced time to progression and survival in breast cancer. The gpNMB-targeting antibody, CR011, is linked to a potent cytotoxic, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. Glembatumumab vedotin is designed to be stable in the bloodstream but to release MMAE upon internalization into gpNMB-expressing tumor cells, resulting in a targeted cell-killing effect. Glembatumumab vedotin is in development for the treatment of locally advanced or metastatic breast cancer with an initial focus in triple negative disease, stage III and IV melanoma, squamous cell lung cancer, uveal melanoma and osteosarcoma.