HydraSpace™ Payload-Enhancing Technology
HydraSpace™ is an ADC-enhancing spacer technology that is compatible with our site-specific antibody conjugation technology and offers the following additional advantages:
• Improves ADC stability
• Increases payload solubility
• Improves conjugation efficiency and speed
• Branching capability enables higher drug loading
• Enables “Dual-Warhead” ADCs with two mechanisms of action
Some of the most potent anti-cancer payloads available, such as PBDs and duocarmycins, are also the most hydrophobic and difficult to work with in the context of an ADC. This hydrophobicity can lead to insurmountable manufacturability challenges. HydraSpace™ was designed with exactly this in mind and facilitates facile and efficient conjugation of one or multiple highly hydrophobic payloads per conjugation event.
Comprised of a small, highly-polar spacer subunit, HydraSpace™ can be placed at one or multiple locations in the ADC linker-payload. When placed near the payload, HydraSpace™ acts to reduce the local hydrophobicity, essentially pulling the payload into solution and enhancing the biophysical properties of both the payload and that of the resulting ADC.
Increased Drug Loading
The presence of 2 native glycan anchor points per antibody inherently limits GlycoConnect™ to a drug-antibody ratio of 2:1 (DAR2); however the unique branching capability that is afforded by our HydraSpace™ spacer technology enables multiple drugs to be efficiently attached at each glycan through a single conjugation event. This approach retains the high stability of the native glycan position and ensures that no new, potentially immunogenic epitopes are introduced in the antibody.
Possible ADC formats include:
• DAR2+2 (Dual-Warhead)
Dual-Warhead ADC Product Candidates
The same branching format that enables higher drug loading also enables dual-warhead ADCs (DAR2+2).
Dual-Warhead ADCs offer significant promise for the treatment of resistant, difficult-to-treat forms of cancer given the increased efficacy attainable by combining multiple mechanisms of action into a single ADC product. This is achieved by attaching two different toxin types to the same antibody which are then delivered directly to the same cancer cell.
Although dual-warhead ADCs represent a logical evolutionary step in the field of these targeted cancer therapeutics, they did not represent a viable approach to a product candidate until HydraSpace™ was reduced to practice by Synaffix.
Initial data resulting from our dual-warhead ADCs suggest the potential for a synergistic ADC efficacy profile compared to an equally drug-loaded antibody that wields only one mechanism of action. With the advent of HydraSpace™, a wide variety of dual-warhead ADC combinations are possible to further optimize the efficacy of this potent and selective therapeutic class.