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A wholly owned subsidiary of Eli Lilly and Company
The challenges
Antibody Drug-Conjugates (ADCs) are among the fastest growing drug classes in oncology.
ADCs consist in three components: an antibody that targets the tumor-associated antigen of interest, a potent cytotoxic drug called a payload and a linker that connects the antibody and the drug through a chemical bond.
The primary goal of ADCs is to improve the therapeutic index of chemotherapeutic agents by restricting their systemic delivery to cells that express the antigen targeted by the antibody bearing the drug.
Current generations of ADCs are limited by their very design that narrows their therapeutic window.
Key Challenge: Managing the Hydrophobicity
Most of the challenges with ADCs are related to the hydrophobicity of the cytotoxic drugs used, which degrades the pharmacological properties of the antibody when bound to it.
The PSARLink™ platform is a unique stealth technology that "masks" the hydrophobicity of the cytotoxic drugs by adding a polysarcosine chain to the linker.
Due to the intrinsic hydrophobicity of the drug-linkers used in ADCs, moderate (2-4) DAR (drug-antibody ratio) values have until recently been considered optimal to obtain efficient ADCs with acceptable pharmacological properties when using microtubule inhibitors (auristatins, maytansinoids) or DNA alkylating agents (calicheamicin, pyrrolobenzodiazepines, duocarmycins).
ADCs generated using the PSARLink™ platform, even with a DAR of 8, have similar pharmacokinetics profile as the native antibody.
Impact on Safety
The enhanced hydrophilicity reduces the off-target catabolism and the risk of systemic toxicity. In addition, the state-of-art linker stability of the platform avoids a premature payload release and the associated systemic toxicity.
Enhanced Efficacy
A shorter ADC half-life means lower drug exposure and limited efficacy. By restoring the native antibody properties, ADCs of the PSARLink™ platform have a prolonged half-life leading to an improved drug exposure.
The linker stability, avoiding a premature payload release, also enables the ADCs to direct more drug to the tumor site. PSARLink™ also enables the use of more hydrophobic payloads resulting in a higher bystander effect by enlarging the cytotoxic effect to neighbouring cancer cells, which may not express the tumor-associated antigen (TAA). The bystander effect is key to efficiently address solid tumors which are often heterogenous in terms of TAA.
Preclinical data presented by Mablink in scientific congresses and papers show promising proof-of-concept results for the PSARLink™ platform.
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