PSARlink: a universal ADC technology platform
The PSARlink hydrophilic drug-linker platform is universal and can be adapted to all types of linkers architectures and drugs compounds in order to improve the manufacturability and therapeutic indexes of ADCs.
Our technology is compatible with both native unmodified monoclonal antibodies (DAR8 or DAR16 homogeneous conjugates) or re-engineered antibodies incorporating conjugations tags (DAR2 or DAR4 conjugates). PSARlink is made of units of polysarcosine, which length can be adjusted to mask the hydrophobicity of any type of drugs, even the most hydrophobic. Both cleavable and non-cleavable linkers are compatible.
Even if the use of ADCs for non-oncology indications is still in its infancy, novel approaches are emerging using non-cytotoxic drugs as payloads (e.g. synthetic glucocorticoids for inflammatory diseases or antibiotics for bacterial infections). These news payloads are often less potent than their cytotoxic counterparts used in oncology and can be significantly more hydrophobic. This new subclass of ADCs can strongly benefit from the increased hydrophilicity and drug-loading properties of the PSARlink platform.
3 major features of PSARlink technology
#1 – Masking hydrophobicity and improving pharmacological properties
PSARlink is based on a proprietary monodisperse polysarcosine (PSAR) chemical entity that is orthogonally integrated into the ADC drug-linker structure. The PSAR unit is highly hydrophilic and confers hydrophobicity masking properties and “hydrophilic shielding” of the drug payload. The length of the PSAR unit can be tuned according to the level of hydrophobicity of the drug. The PSAR unit itself is easily accessed at high-scale.
The improved hydrophilicity confers to the ADC:
- An increased efficacy by improving pharmacokinetic properties (increased plasmatic exposure times and tumor accumulation)
- A higher potency by increasing the drug-load up to DAR8 or DAR16. This is particularly useful in the case of low-expressed tumor antigens or innovative drugs with new mechanisms of action lacking the extreme potency of “conventional” ADC payloads.
- An improved toxicity profile, by decreasing non-antigen mediated clearance of the ADC. Hydrophobic ADCs are more quickly cleared by the immune system, leading to dose-limiting toxicities (liver toxicity, neutropenia…).
#2 – Stability and homogeneity
Straightforward attachment of the PSARlink drug-linker to the native inter-chain disulfide bonds of the monoclonal antibody provides an homogeneous DAR8 ADC. Contrary to common belief, full reduction of the inter-chain disulfide bonds of an IgG does not induce destabilization of the antibody structure, aggregation, loss of binding affinity or negatively impact pharmacokinetics. This is notably exemplified by the fact that several soon-to-be-approved ADCs (late Phase III) are fully reduced topoisomerase inhibitor-based DAR8 ADCs. If required and if relevant, an homogeneous DAR16 ADC can also be produced using a divalent PSARlink drug-linker.
Any conjugation chemistry can be implemented with the PSARlink ADC platform (maleimide and self-hydrolyzable maleimides, iodoacetamide, primary amine, oxime, peptidic motif such as poly-glycine…). As a result, the PSARlink technology can also be paired with proprietary site-specific conjugations technologies in order to produce homogeneous DAR2 or DAR4 conjugates if needed.
Plasma stability is assured by the use of an auto-hydrolyzable maleimide moiety as the conjugation handle in the linker. This prevents premature release of the cytotoxic payload in the bloodstream.
#3 – Timely and cost effective
PSARlink platform is universal, virtually adaptable to any native antibody and compatible with any cytotoxic compound. It does not require time-consuming re-engineering of the antibody and enables the production of ADCs in a timely and cost-effective manner. The platform is perfectly suited for rapid screening of several monoclonal antibodies with an ADC potential.