Antibody Drug Conjugate Targeting CLDN1 Receives FDA Fast Track Designation

ALE.P02 (Alentis Therapeutics), an investigational antibody-drug conjugate (ADC) targeting anti–claudin-1 (CLDN) received FDA fast track designation for the treatment of advanced or metastatic CLDN1+ squamous cancers irrespective of the organ of origin. ALE.P02 could provide treatment for lung, head and neck, cervical, and esophageal CLDN1+ squamous cancers, but is not limited to additional cancers.¹

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"Squamous cancers of various origin have been shown to overexpress CLDN1, making ALE.P02 a promising ADC to address the unmet medical needs of these patients," Tony Mok, a professor of Clinical Oncology at the Chinese University of Hong Kong, said in a press release. "CLDN1 is an exciting new target for ADCs and Alentis has been the frontrunner in developing anti-CLDN1 therapeutics."¹

The first-in-class ADC includes a tubulin inhibitor that is linked to an antibody that was designed to target a unique CLDN1 epitope exposed on cancer cells. The treatment combination could be essential in attacking various squamous cancers that overexpress CLDN1, while providing less toxicity than standard cancer drugs.¹

ADCs differ from chemotherapy and other cancer drugs as they can selectively target and kill tumor cells without restricting anti-cancer activity. Other cancer drugs typically have low specificity towards tumor cells, which provide substantial toxicity to normal healthy tissues. Additionally, in healthy cancer cells, CLDN1 is hidden in tight junctions, and its normal function is to bind with other healthy cells. However, solid tumors can overexpress CLDN1, where it is exposed outside of the normal junctions. This allows CLDN1 to be recognized by the anti-CLDN1 antibody on tumor cells without impacting the healthy tissue, making it a potential tumor target.²

"We have set out to develop ALE.P02 in the most rational way, following CLDN1 science and the clinical understanding of squamous cancers. The FDA’s support in this endeavor is certainly motivating," Luigi Manenti, chief medical officer of Alentis, said in a press release.¹

In October 2024, the FDA cleared an investigational new drug application for ALE.P02, which allowed initiation of a first-in-human phase 1/2 trial assessing ALE.P02 in individuals with CLDN1-postive squamous solid tumors. The study authors noted that the trial is aimed to begin in the first quarter of 2025.³

"We are optimistic about the potential of ALE.P02 and look forward to the start of our first-in-human clinical trial in Q1 2025,” Manenti said in a press release.¹

Alentis Therapeutics is also developing ALE.P03, an additional ADC that is similar to ALE.PO2, which utilizes a CLDN1-targeting antibody to selectively bind and internalize into CLDN1-postive tumors cells. However, ALE.P03 is engineered with a topoisomerase I inhibitor ADC, as ALE.P02 uses a tubulin inhibitor ADC.²

Preclinical trials demonstrated selective binding and internalization in CLD1+ tumor cells, leading to strong tumor growth across different tumors models with CLDN1 expression levels in vivo, with ALE.P02 and ALE.P03.²

Aside from the upcoming phase 1/2 study evaluating ALE.P02, toxicology studies for ALE.P03 are ongoing.²

“We are encouraged by the FDA’s recognition of ALE.P02’s potential as a treatment for CLDN1+ squamous cancers," Roberto Iacone, chief executive officer of Alentis Therapeutics, said in a press release. "It reflects the importance of advancing ALE.P02 through clinical development, and it brings us one step closer to providing a new treatment option for patients.”¹

REFERENCES

1. Alentis Receives FDA Fast Track Designation for ALE.P02 for the Treatment of CLDN1+ Squamous Solid Tumors. News release. Alentis Therapeutics. November 18, 2024. Accessed November 21, 2024. https://www.businesswire.com/news/home/20241118754051/en

2. ALE.P02 & ALE.P03 ADCs for Claudin-1 positive tumors. News release. Alentis Therapeutics. Accessed November 21, 2024. https://alentis.ch/ale-p02-ale-p03-adcs-for-claudin-1-positive-tumors/.

3. Alentis Therapeutics Receives FDA IND Clearance for ALE.P02, a Novel CLDN1-ADC for the Treatment of Squamous Cancers. News release. Alentis Therapeutics. October 2, 2024. Accessed November 21, 2024. https://alentis.ch/alentis-therapeutics-receives-fda-ind-clearance-for-ale-p02-a-novel-cldn1-adc-for-the-treatment-of-squamous-cancers/.