Shanghai-based biopharmaceutical company Antengene, confirmed that ATG-022, a Claudin 18.2 (CLDN18.2) antibody drug conjugate (ADC) being developed by the company, has been granted two Orphan Drug Designations (ODD) consecutively by the U.S. Food and Drug Administration (FDA) for the treatment of gastric cancer and pancreatic cancer.

The drug conjugates IMAB362, an antibody targeting Claudin 18.2, via a valine-citrulline (vc-) type linker (mc-vc-PABC-MMAE)* to the antimitotic agent, monomethyl auristatin E (MMAE)

Targeted cancers
Gastric cancer is malignancy arises in the gastric epithelium. According to the statistic for 2019 of the World Health Organization’s (WHO), gastric cancer was ranked the ninth by mortality among all cancers. In 2022, there were an estimated 26,000 gastric cancer diagnoses and 11,000 gastric cancer-related death in the U.S. The current 5-year survival of patients with metastasized and local gastric cancers are 70% and 32%, respectively.[1]

Pancreatic cancer is a highly malignant type of gastrointestinal cancer. According to the statistics of the World Health Organization (WHO), pancreatic cancer was ranked 13th and 7th globally by its incidence rate and mortality rates in 2012. In 2018, the U.S. reported over 55,000 newly- diagnosed pancreatic cancer cases and 44,330 related deaths. Whereas pancreatic cancer is still defined as an orphan disease currently, it is projected that by 2030, pancreatic cancer will become the second most common cause of cancer-related deaths.

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Targeting Claudin 18.2
ATG-022 targets Claudin 18.2.  Claudins are cell adhesion molecules normally expressed within the tight junctions between cells to form a barrier that regulates cell permeability. In cancer, Claudins are expressed at the cell surface due to changes in cell polarity.

The Claudin 18.2 isoform is over-expressed in various primary malignant tumors including gastric, esophageal and pancreatic cancers. The Phase I CLINCH study of ATG-022 in patients with advanced or metastatic solid tumors, already approved by the China National Medical Products Administration (NMPA) and Bellberry Human Research Ethics Committee (HREC) in Australia, is currently ongoing in China and Australia.

Data from preclinical studies, including results from gastric cancer-patient derived xenograft models presented at the annual meeting of the American Association for Cancer Research (AACR), held April 8-13, 2022 in New Orleans LA., showed that ATG-022 binds to Claudin 18.2 with low nanomolar (nM) affinity and demonstrated potent in vitro and in vivo antitumor effects, including in vivo efficacy demonstrated in Claudin 18.2 low expression models.

The results further demonstrated that ATG-022 induced potent in vitro cytotoxicity in CHOK1 cells overexpressing CLDN18.2, with an IC50 of 5-7nM. In addition, bystander killing by ATG-022 was observed. ATG-022 demonstrated potent in vivo antitumor efficacy in a gastric cancer PDX model with high CLDN18.2 expression. Based on these observations, the study’s investigators believe that ATG-022 could pave the way for broad clinical utility  in gastric cancer patients with a wide range of Claudin 18.2 expression levels.[1]

In addition to these preclinical outcomes, ATG-022 demonstrated an excellent safety profile in Good Laboratory Practice (GLP) toxicology studies.[1]

Orphan drugs
Orphan Drugs, also known as Rare Disease Drugs, refers to pharmaceutical products developed for the prevention, diagnosis, and treatment of rare diseases or conditions. Orphan Drug Designations by the U.S. FDA are meant to support the development of drug candidates that could potentially bring substantial therapeutic benefits to patients with rare diseases (a condition with a prevalence of less than 200,000 in the U.S.), and to provide incentives to the subsequent development, registration and commercialization to designated drugs. Those incentives include tax credit on expenditures incurred in clinical studies, a waiver of the New Drug Application (NDA) fee, and 7-year market exclusivity in the U.S. regardless of the patent status of the designated drug.

“We believe the that Orphan Drug Designation represents an important regulatory milestone for ATG-022, recognizing the significant and urgent unmet need for new treatments to help patients who are fighting difficult to treat and devastating diseases such as pancreatic and gastric cancers,” explained Amily Zhang, MD, Antengene’s Chief Medical Officer.

“We are enthusiastic about the potential for ATG-022 to treat gastric and pancreatic cancers. Moving forward, Antengene will work closely with regulators and clinical investigators to advance the CLINCH trial and fully assess ATG-022’s therapeutic potential for solid tumors,” Zhang concluded.

Note: * ATG-022 includes a maleimidocaproyl (mc) spacer, a protease-sensitive dipeptide, valine-citrulline (vc), a self-immolative spacer, para-amino benzyloxycarbonyl (PABC).

Clinical trials
A Study of ATG-022 in Patients With Advanced/Metastatic Solid Tumors (CLINCH) – NCT05718895

[1] Chen P, Liu Y, Deng M, Tian L, Lynch K, Shan B, Jay Mei, Bing Hou. ATG-022, an antibody-drug conjugate targeting Claudin 18.2, demonstrated potent in vivo efficacy in gastric cancer patient-derived xenografts In: Proceedings of the 113th Annual Meeting of the American Association for Cancer Research; 2022 April 8-13; New Orleans LA. Philadelphia (PA): AACR; 2022. Abstract nr 1143 / 7

Featured image Getty Images Licensed under the Unsplash+ License. Used with permission.

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