Preclinical data of a novel ADC being developed by Elevation Oncology, demonstrated proof-of-concept for its differentiated HER3-ADC program.  The data was presented in a poster session at the American Association for Cancer Research (AACR) Annual Meeting 2024, being held April 5-10 in San Diego, California.[1]

“We are pleased to share the first preclinical proof-of-concept data for our HER3-ADC program, reinforcing our commitment to advancing a portfolio of differentiated ADC-based therapies that may deliver better outcomes for patients,” said David Dornan, Ph.D., Chief Scientific Officer of Elevation Oncology.

“With our HER3-ADC program, we set out to design a differentiated ADC which selectively binds to HER3 and is internalized to potentially attack HER3-expressing cancerous cells while minimizing systemic exposure. Preclinical data with our proof-of-concept HER3-ADC shows HER3-dependent cell killing and robust anti-tumor activity in vivo where HER3 is expressed at high levels.  We look forward to nominating a development candidate from our HER3 program later this year and, subsequently, advancing our program closer to the clinic.”

HER3
The HER3 protein, that belongs to the ErbB/HER receptor tyrosine kinase (RTK) family, is expressed in several types of tumors and is a clinically validated target in oncology and used in the development of novel antibody-drug conjugate (ADC). It is overexpressed in a range of solid tumors, including breast cancer, EGFR-mutant non-small cell lung cancer and pancreatic cancer, and is often associated with poor clinical outcomes.[1][2]

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There are currently no HER3-targeted ADC agents approved for the treatment of cancer.

Elevation Oncology’s HER3-ADC program conjugated seribantumab (MM-121), the company’s a fully human IgG2 anti-HER3 monoclonal antibody, with a cleavable valine-citrulline linker and monomethyl auristatin E (MMAE) payload to yield HER3-ADC, a proof-of-concept molecule with an average drug-antibody ratio (DAR) of 4.

Proof of Concept
In the proof-of-concept study, Elevation Oncology’s HER3-ADC was evaluated in vitro and in vivo, with patritumab deruxtecan*, a HER3 targeting ADC being developed by Daiichi Sankyo and Merck/MSD, as a comparator.  In vitro cytotoxicity was evaluated for HER3-ADC, isotype-MMAE and free MMAE payload as well as patritumab deruxtecan.[3]

Data presented included in vitro and in vivo data of a seribantumab-based ADC for patients with HER3-expressing cancers. The data showed:

  • HER3-ADC binding to cancer cells, endocytosis, MMAE release and inhibition of proliferation were dependent on HER3 expression.
  • In cytotoxicity assays, HER3-ADC displayed HER3-dependent cell killing and outperformed a benchmark HER3-ADC with a deruxtecan payload, which is currently in clinical development.
  • In a patient derived xenograft (PDX) model of pancreatic cancer with high HER3 expression, HER3-ADC induced tumor regression, whereas an isotype-MMAE control and a benchmark HER3-ADC with a deruxtecan payload had only a modest effect.

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Note: The U.S. Food and Drug Administration (FDA) granted Priority Review to the Biologics License Application (BLA) for patritumab deruxtecan for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) previously treated with two or more systemic therapies. The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is June 26, 2024. The Priority Review follows receipt of Breakthrough Therapy Designation granted by the FDA in December 2021.

Reference
[1] Thomas O’Hare, Jaclyn Cleveland, Valerie M. Jansen, David Dornan. Therapeutic potential of a HER3 antibody-drug conjugate for the treatment of HER3-expressing cancers  [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3121.
[2] Gandullo-Sánchez L, Ocaña A, Pandiella A. HER3 in cancer: from the bench to the bedside. J Exp Clin Cancer Res. 2022 Oct 21;41(1):310. doi: 10.1186/s13046-022-02515-x. PMID: 36271429; PMCID: PMC9585794.
[3] Koyama K, Ishikawa H, Abe M, Shiose Y, Ueno S, Qiu Y, Nakamaru K, Murakami M. Patritumab deruxtecan (HER3-DXd), a novel HER3 directed antibody drug conjugate, exhibits in vitro activity against breast cancer cells expressing HER3 mutations with and without HER2 overexpression. PLoS One. 2022 May 3;17(5):e0267027. doi: 10.1371/journal.pone.0267027. PMID: 35503762; PMCID: PMC9064083.

Featured image: Poster session during the 2019 Annual Meeting of the American Association for Cancer Research Annual Meeting. Photo courtesy:  © 2019 – 2024 AACR/Todd Buchanan

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