HER2 ADC(Araris)

A novel therapeutic approach that combines human epidermal growth receptor factor 2 (HER2)-targeted therapies with the cholesterol-lowering drug lovastatin can reduce the number of cancer treatments required to prevent tumor growth. Monitored by immuno-PET scans, this combination therapy has the potential to personalize treatment for cancer patients and spare them from harmful side effects. A novel therapeutic approach that combines human epidermal growth receptor factor 2 (HER2)-targeted therapies with the cholesterol-lowering drug lovastatin can reduce the number of cancer treatments required to prevent tumor growth. Monitored by immuno-PET scans, this combination therapy has the potential to personalize treatment for cancer patients and spare them from harmful side effects. This research was published in the October issue of The Journal of Nuclear Medicine. Antibody-drug conjugates (ADCs) have become an eminent cancer treatment because of their ability to precisely target tumors with potent efficacy. HER2-ADC therapies have been effective in treating breast, lung, bladder, and stomach cancers. Although they are usually well-tolerated, multiple doses of the drugs can result in severe side effects, including low blood counts, liver damage, and lung damage. Strategies that reduce toxic side effects caused by ADCs and predictive biomarkers of ADC toxicity are currently an unmet clinical need. "In this study, we sought to determine whether a single dose of HER2-ADCs could be administered in combination with lovastatin (which temporarily elevates cell-surface HER2) to achieve therapeutic efficacy similar to that of a multiple dose regime," said Patricia Pereira, PhD, assistant professor at the Mallinckrodt Institute of Radiology at the Washington University School of Medicine in St. Louis, Missouri. "We also used HER2-targeted immuno-PET to monitor changes in HER2 expression after ADC therapy." Researchers injected mice with cultured gastric cancer cells and patient-derived gastric cancer cells. When tumors grew sufficiently, the mice were divided into groups and received various treatment schedules (no treatment, multiple doses of ADC, multiple doses of ADC with lovastatin, single dose of ADC, or single dose of ADC with lovastatin). Immuno-PET was used to investigate the dosing regimen and the efficacy of the treatment schedules. A single dose of ADC therapy combined with lovastatin was found to reduce tumor volume at rates similar to those resulting from multiple doses of ADC in a preclinical setting. The study results showed that immuno-PET can noninvasively monitor HER2 tumor levels after treatment with HER2-targeted ADC therapies. "This preclinical work is significant because it has the potential to improve therapy for patients with HER2-positive cancers," noted Pereira. "It not only simplifies treatment by exploring single-dose schedules of antibody-drug conjugates but can also reduce side effects by minimizing the number of doses required. Additionally, it personalizes therapy using molecular imaging, enhancing treatment efficacy." She continued, "The findings suggest a future where molecular imaging techniques play a critical role in guiding drug development and cancer treatment decisions, particularly as various ADCs are being tested and approved for cancer treatment. Currently, there is no perfect way to select tumors or monitor their response to ADCs. This research indicates that molecular imaging can bridge this gap by providing real-time insights into therapy response." This study was made available online in June 2023.

Submission Follows Positive Results of Phase III TULIP® Trial Next Generation HER2-ADC Uses Byondis Technologies Aimed at Improving Treatment Outcomes NIJMEGEN, Netherlands, July 12, 2022 /PRNewswire/ -- Byondis B.V., an independent, Dutch clinical stage biopharmaceutical company creating precision medicines, announced today that the U.S. Food & Drug Administration (FDA) accepted the company's submission of a Biologics License Application (BLA) for [Vic-] Trastuzumab Duocarmazine (SYD985) in patients with HER2-positive unresectable locally advanced or metastatic breast cancer (MBC). The company has been given a Prescription Drug User Fee Act (PDUFA) action date of May 12, 2023. SYD985 is an investigational next generation anti-HER2 antibody-drug conjugate (ADC) that was granted fast track designation by the FDA in January 2018 based on promising Phase I data involving heavily pretreated last-line HER2-positive MBC patients (SYD985.001/NCT02277717). "Women with HER2-positive breast cancer generally have a more aggressive disease, greater likelihood of recurrence and poorer prognosis," said Byondis Chief Medical Officer Jan Schellens, M.D., Ph.D. "Today's SYD985 BLA acceptance by the FDA is an important step forward toward our goal of providing a much-needed alternative for these patients." In HER2-positive breast cancer, overexpression of the human epidermal growth factor receptor 2 (HER2) protein causes out-of-control reproduction of breast cells. Less than 20 percent of all breast cancers are HER2-positive, with younger women being the most affected.1 "With our proprietary technologies, we aim to offer antibody-drug conjugates with a novel mechanism-of-action, which are still efficacious when other ADC therapies have been exhausted," said Byondis CEO Marco Timmers, Ph.D. "SYD985 combines a HER2-targeting antibody with a novel and potent cytotoxic drug in a way that limits damage to healthy tissue." This is Byondis' first regulatory submission for its lead program SYD985. The BLA is supported by data from the pivotal Phase III TULIP® multi-center, open-label, randomized clinical trial comparing SYD985 to physician's choice (PC) treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer (SYD985.002/NCT03262935). The study, of which the results were presented at the 2021 ESMO Congress, met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement of 2.1 months over PC. TULIP also demonstrated supportive overall survival (OS) results. [Vic-]Trastuzumab Duocarmazine (SYD985), a Next Generation Antibody-Drug Conjugate [Vic]-trastuzumab duocarmazine (SYD985) incorporates Byondis' distinctive, proprietary duocarmazine linker-drug (LD) technology ByonZine®. The ADC is comprised of the anti-HER2 monoclonal antibody trastuzumab and a cleavable linker-drug called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). The antibody part of trastuzumab duocarmazine binds to HER2 on the surface of the cancer cell and the ADC is internalized by the cell. After proteolytic cleavage of the linker, the inactive cytotoxin is activated and DNA damage is induced, resulting in tumor cell death. SYD985 is considered a form of targeted therapy. ByonZine®, Byondis' Distinctive, Proprietary Linker-Drug Technology While earlier generation ADCs improved targeting and cell killing, they were unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. Byondis' next generation ADCs are highly stable in circulation and carry an intricate, inactivated and potent cytotoxic drug that rapidly self-destructs if it is prematurely released, limiting damage to healthy tissue and improving the therapeutic window. Byondis' differentiated linker-drug, vc-seco-DUBA, owes its potent antitumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and disrupt the nucleic acid architecture, which eventually leads to tumor cell death. The distinctive design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces efficient release of the cytotoxin in the tumor. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression may improve the efficacy potential, the so-called bystander effect. About Byondis Driven to improve patients' lives, Byondis is an independent, privately held, Dutch clinical stage biopharmaceutical company creating innovative precision medicines targeting intractable cancers and autoimmune diseases. The company is developing next generation antibody-drug conjugates (ADCs) using its proprietary molecular concepts such as ByonZine®, its duocarmazine linker-drug (LD) technology, and ByonShieLD®, its site-specific conjugation technology. It is also creating monoclonal antibodies (mAbs) and new chemical entities (NCEs) that can stand alone or be incorporated in its ADCs. Byondis' broad development portfolio comprises preclinical as well as early- and late-stage clinical development programs. The company has a dedicated team of about 400 employees, including highly educated scientists and skilled technicians working in state-of-the-art R&D and Good Manufacturing Practice (GMP) production and conjugation facilities on its campus in Nijmegen, the Netherlands. Byondis regularly collaborates with leading global biotechnology and pharmaceutical companies, as well as many academic research institutions. For more information, visit . 1Cherney Kristeen. "What Is HER2-Positive Breast Cancer? Understanding Your Outlook." Healthline.com, 9 March 2022, accessed 15 June 2022 SOURCE Byondis B.V.