Adagene, a platform-driven, clinical-stage biopharmaceutical company committed to transforming the discovery and development of novel antibody-based immunotherapies, today announced that it has entered into a third clinical trial collaboration and supply agreement with Merck & Co.

The agreement includes an open-label, dose-escalation and expansion clinical study of ADG106 in combination with Merck’s anti-PD-1 pembrolizumab (Keytruda®, Merck & Co/ Merck Sharp & Dohme) in advanced or metastatic solid and/or hematological malignancies. This clinical study builds on the promising monotherapy and combination therapy data from a Phase I trial of ADG106.

NEObody™ platform technology
Adagene’s NEObody™ technology is a fully synthetic phage display and yeast display-based antibody discovery technology. According to the platform’s developers, this technology is differentiated from other synthetic antibody technologies due to its innovative designs and precise constructions. Tge technology allowes scientists to discover antibodies targeting numerous epitopes against a broad range of antigens.

Engineered using Adagene’s proprietary NEObody™ platform technology, ADG106 is a fully human, ligand-blocking, agonistic anti-CD137 immunoglobulin G4 (IgG4) monoclonal antibody being developed for the treatment of advanced solid tumors and non-Hodgkin’s lymphoma.

CD137 (4-1BB), a surface glycoprotein, is a member of the tumour necrosis factor receptor family (TNFRSF9) that stimulates the immune system to attack cancer cells and is known to be a key driver for long-lasting T-cell proliferation and survival. Its expression is induced on activation on a number of leucocyte types.

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In cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Research investigationg the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists.

In preclinical studies, scientists at Adagene observed that ADG106 had robust antitumor activity and was well tolerated as a single agent and in combination with the existing standard-of-care and other immuno-oncology therapies. ADG106 activates CD137 in a native ligand-like fashion, blocks reverse CD137 ligand signaling, and induces potent cross-linking by Fc receptors. Because of this novel mechanism of action, ADG106 was observed to favorably balance CD137 agonism over CD137-induced liver toxicity, which we believe has potential to address the limitations of other existing anti-CD137 therapies.[1]

Clinical development
ADG106 Phase I trials have been successfully completed with enrollment of nearly 100 patients with advanced solid tumors and non-Hodgkin’s lymphoma in the United States and China. Based on the promising Phase I data, ADG106 is being evaluated in a Phase Ib/II combination study in advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma.

Phase I data
Earlier this year, results from Phase I, open-label, dose-escalation, single center and multicenter studies of ADG106 in patients with advanced or metastatic solid tumors and/or relapsed/refractory non-Hodgkin lymphoma were presented in an abstract at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting. In these Phase I trials, ADG106 monotherapy exhibited a favorable safety profile and demonstrated promising clinical efficacy in biomarker positive patients.[1]

“ADG106 has been well tolerated in dose escalation and extensive expansion cohorts at dosage of up to 5 mg/kg, which exceeds that of other anti-CD137 agonists. Further, this clinical data demonstrates the power of our proprietary NEObody platform designed to generate antibodies with novel mechanisms of action by targeting unique and highly conserved epitopes. We believe these results, together with analyses of PK and PD data from around 100 patient population, support the recommended dose regimen for ongoing clinical development of ADG106 as monotherapy and in combination with anti-PD-1 and other therapies.”

Partnership with Merck
“We are excited to continue our partnership with Merck in a third clinical collaboration that now combines our anti-CD137 agonist, ADG106, with pembrolizumab,” said Peter Luo, Ph.D., Co-founder, Chief Executive Officer, and Chairman of Adagene.

“While PD-1 drugs have advanced the cancer treatment paradigm, there are still a substantial number of patients with advanced metastatic solid and hematological malignancies who either relapse or are unresponsive, highlighting the need for new approaches. ADG106 targets a unique and highly conserved epitope with a novel mechanism of action and broad species cross-reactivity, which enables testing in immunocompetent hosts. In multiple syngeneic models, we have shown a strong additive effect between ADG106 and anti-PD-1/PD-L1 agents,” Luo added.

“We look forward to working closely with Merck and combining ADG106 with pembrolizumab,” said Steven Fischkoff, M.D., interim Chief Medical Officer of Adagene.

“Together with our novel mechanism of action, extensive preclinical and strong clinical data generated to date, we believe ADG106 is an ideal candidate to combine with an anti-PD1 antibody to potentially create a new therapeutic option for cancer patients with unmet medical needs,” Fischkoff concluded.

Clinical Trials
Study of ADG106 In Combination With PD-1 Antibody In Advanced or Metastatic Solid Tumors and/or Non Hodgkin Lymphoma – NCT04775680
Study of ADG106 With Advanced or Metastatic Solid Tumors and/or Non-Hodgkin Lymphoma – NCT03802955
Study of CD137 Agonist ADG106 With Advanced or Metastatic Solid Tumors and/or Non-Hodgkin Lymphoma – NCT03707093

Highlights of Prescribing Information
Pembrolizumab (Keytruda®, Merck & Co/ Merck Sharp & Dohme)[Prescribing Information]

[1] Zhang L. Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials. Journal of Clinical Oncology 2021 39:15_suppl, e14505-e14505 [Publication]
[2] Etxeberria I, Glez-Vaz J, Teijeira Á, Melero I. New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis. ESMO Open. 2020 Jul;4(Suppl 3):e000733. doi: 10.1136/esmoopen-2020-000733. PMID: 32611557; PMCID: PMC7333812.

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