The goal of the research was to generate novel, therapeutic bispecific antibodies against solid tumors. In cancer patients, the immune system’s ability to eradicate the tumor is suppressed. Antibodies are proteins produced by the immune system to combat disease, and they can be manipulated and engineered in the lab to target specific proteins and cell types. Bispecific antibodies are those that have dual targeting arms in the same molecule. In the context of cancer, bispecific antibodies can address the shortcomings of the immune system in its task of recognizing and eliminating cancer cells.
Syngene enabled a client strategy to discover and design novel, bispecific antibodies. In this approach, one arm identifies and binds the tumor-specific antigen and the second arm recruits and activates specific immune cells (T-cells) within the tumor with the intent of killing it Refer Figure 1.
Syngene scientists have enabled a unique bispecific platform for a client. Syngene was involved in all aspects of discovery including design, execution and candidate molecule selection. Within the exceptionally short timeframe of 1.5 years for this collaboration, scientists discovered and engineered four lead bispecific antibodies against different solid tumors, all of which are being taken forward for pre-clinical Investigational New Drug (IND) enabling studies.
The overall workflow for this research program involved design and production of target cancer antigens, immunization of mice, antibody discovery by hybridoma technology, screening for novel binders, sequencing of the variable regions (the biologically active end of the molecule), engineering the sequences into a bispecific format, production, stability testing, and functional studies in cell lines and in animal models. The antibodies that pass all the criteria of potency, stability, and efficacy are progressed to preclinical safety assessment and subsequent IND filing.
In the initial stage, Syngene scientists focused on identifying the antibody sequence crucial for targeting the tumor. Using tumor antigens, the sequence of one arm of the antibody was determined. The sequence for the second arm is derived to target a specific type of immune cell through a similar process.
Once both the sequences are obtained, the antibodies are manufactured and then evaluated for potency, stability, and efficacy. Those meeting the criteria advance to preclinical safety assessment and subsequent filing for Investigational New Drug (IND) approval.
Figure 1: Cartoon representing a bispecific antibody approach used by Syngene scientists for targeted immune cell activation against cancer cell.
Figure 2: Data showing effective cancer cell killing by lead bispecific antibody compared to null arm (tumor binding arm is absent) negative control.
Bispecific antibodies are an emerging platform of biotherapeutics with six approved drugs and hundreds in clinical trials. Syngene scientists discovered several lead bispecific antibody molecules in a short period of time against four discrete tumor types by designing and executing experiments to evaluate potency, stability and functional efficacy in the preclinical setting.
These molecules are being further evaluated for suitability for advancement into Phase I human clinical trials. Discovery of this nature requires a seamless partnership between several functions including the protein sciences, antibody discovery, assay biology, and in vivo pharmacology teams within Syngene along with client’s tech team.
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Brinkmann U, Kontermann RE.; MAbs. 2017 Feb/Mar;9(2):182-212. PMID: 28071970.
Bispecific Antibodies: An Area of Research and Clinical Applications; August 02, 2023; FDA report in News and Events for human drug.
