Jan Schellens, MD, CMO Byondis discusses the Phase I Study of Antibody-Drug Conjugate SYD1875.
11 August 2020, Nijmegen, The Netherlands, Byondis B.V. (formerly Synthon Biopharmaceuticals B.V.) today announced that treatment with its investigational antibody-drug conjugate (ADC) SYD1875 was initiated by the first cancer patients.
In patients with 5T4-expressing, locally advanced or metastatic solid tumors, the First-in-Human Dose-Escalation and Expansion Trial with the Antibody-Drug Conjugate SYD1875 will assess the safety, pharmacokinetics, and preliminary efficacy of SYD1875. While 5T4 plays an important role in cancer growth, there are currently no drugs that target this particular tumor antigen. Patients are currently registered at leading European oncology centers: Jules Bordet Institute in Brussels, Belgium; Bergonié Institute in Bordeaux, France; and Oscar Lambret Center in Lille, France.
"It is exciting and gratifying to hear that SYD1875 has advanced to the clinical study level, giving us the opportunity to explore the potential of another successful antibody-drug conjugate," said Marco Timmers, Ph.D., CEO of Byondis. Our ADC technologies are aimed at outsmarting relentless cancers and enhancing patient outcomes by delivering improved tumor-killing properties with lower side effects.
The SYD1875 is the second Byondis ADC to proceed to clinical trials. The company's most advanced anti-HER2 ADC [vic-]trastuzumab duocarmazine (SYD985) targets a number of HER2-expressing cancers, such as metastatic breast cancer and endometrial (uterine) cancer.
More on the analysis SYD1875.001
The research SYD1875.001 will recruit approximately 90 patients aged 18 years and older with histologically confirmed, locally advanced, or metastatic cancers that have progressed with standard therapy or for which there is no standard therapy. The research will be performed in two parts: Escalation and Expansion of the Dose.
In order to evaluate the optimal tolerated dose (MTD) and recommended dose for expansion (RDE), Part 1, Dose Escalation, will enroll patients with any tumor type. Section 2, Dose Expansion would enroll patient groups who have one of three types of cancers. In order to test the effectiveness and safety of SYD1875 in these groups, these patients will receive the RDE determined in Part 1. SYD1875 infusions will be given to all patients in both parts of the study every three weeks before the progression of cancer or inappropriate toxicity.
About SYD1875, a Conjugate Next Generation Antibody-Drug
The special, proprietary linker-drug (LD) and site-specific conjugation technologies of Byondis are used by SYD1875. Although marketed ADCs have improved therapeutic indices relative to traditional non-target chemotherapeutic agents, there is room for improvement still.
SYD1875 is a next-generation ADC consisting of a humanized IgG1 mAb (monoclonal antibody) and a valine-citrulline-seco-DUocarmycin-hydroxyBenzamideAzaindole (vc-seco-DUBA) cleavable linker drug that targets the 5T4 oncofetal antigen using HC-41C site-specific conjugation. The SYD1875 antibody component binds to 5T4 on the cancer cell surface, and the cell internalizes the ADC. The inactive cytotoxin is triggered after proteolytic cleavage of the linker and DNA damage is caused, leading to tumor cell death. It is possible to consider SYD1875 to be a type of targeted chemotherapy.
For the manufacture of SYD1875, this ADC relies on a single-step, selective reduction of the engineered cysteines, rather than a two-step reduction/oxidation protocol that is widely used for these types of ADCs and can lead to undesirable side products.
Special, Patented Linker-Drug and Site-Specific Conjugation Technologies from Byondis
A cytotoxin reaches the bloodstream during standard chemotherapy and travels through the body to destroy rapidly dividing cells that are normal in tumors. The problem is that in normal tissue, it often assaults rapidly dividing cells, possibly resulting in serious side effects.
Monoclonal antibodies are produced by targeting receptors expressed on tumor cell membranes to enable improved specificity. Cytotoxic drugs may be added to the antibodies using a linker molecule, creating antibody-drug conjugates or ADCs to enhance the ability of anticorps to kill cells.
Although earlier-generation ADCs have improved targeting and cell killing, they may be unstable in the bloodstream, leading to the early release of cytotoxic payload, affecting healthy tissue, and decreasing the therapeutic window. The next-generation ADCs from Byondis bears an intricate, inactivated cytotoxic drug that rapidly self-destructs if released prematurely, minimizing damage to healthy tissue and enhancing the therapeutic window.
The differentiating linker-drug byondis, vc-seco-DUBA, owes its potent antitumor activity to a cytotoxin based on synthetic duocarmycin. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the lower groove of DNA and disrupt the architecture of nucleic acid which eventually leads to the death of tumor cells.
The specific nature of the selectively cleavable linker that binds the antibody to the duocarmycin drug results in high circulatory stability and induces the efficient release of the cytotoxin in the tumor. Finally, as was shown in preclinical models, the site-specific conjugation of the linker-drug results in improved in vivo antitumor activity.
On Byondis (formerly Biopharmaceuticals for Synthon)
Byondis is an independent biopharmaceutical research and development company that creates innovative precision medicines targeting intractable cancers and autoimmune diseases, driven to improve the lives of patients. The company is developing new biological entities (NBEs) and new chemical entities (NCEs) and is differentiated by its patented molecular principles from other biopharmaceutical firms, such as its linker-drug (LD) and site-specific antibody-drug conjugate (ADC) conjugation technologies.
The wide portfolio of Byondis' research includes preclinical and early and late-stage clinical programs, including the anti-HER2 ADC [vic-]trastuzumab duocarmazine (SYD985, Phase III). The company has a dedicated team of more than 350 workers employed at its state-of-the-art R&D and GMP production facilities in Nijmegen, the Netherlands, including highly trained scientists and qualified technicians. Byondis collaborates with major biotechnology and pharmaceutical firms and academic research institutions at home and abroad. Visit www.byondis.com for more information.
The SYD1875 study is registered with the identifier NCT04202705 on ClinicalTrials.gov.