4 key factors to design an ADC​

One of the major challenges in the development of an ADC is to generate a therapeutic product with an increased therapeutic index. Mablink has a strong expertise in immuno-oncology, chemistry and pharmacology. We know how to apprehend the different key components of ADC design: the target, the antibody, the cytotoxic payload and the linker. With our PSARlink hydrophilic drug-linker technology, our goal is to propose and help to bring to the clinic better designed 3rd generation ADCs having improved therapeutic indexes. The PSARlink platform also opens the way to the use of innovative “moderately potent” drugs having differentiated mechanism of action or very hydrophobic compounds as ADC payloads.

Target

  • Specific to tumor cells, with no or negligible expression on healthy tissues
  • Ideally, high and homogeneous expression on the surface of the cancer cells
  • The antibody-antigen complex must be internalized
  • Moderately and low-expressed antigens can also be targeted with new approaches

Cytotoxic drug

  • Must be appropriate for the chosen indication (effective against the chosen tumor type)
  • Classic mechanisms of action (microtubule inhibitors & DNA damaging agents) or innovative mechanism of action (topoisomerases inhibitors, KSP inhibitors, NAMPT inhibitors…)
  • Moderately potent payloads (low nM IC50 activities) with innovative mechanism of action requires high drug-antibody ratio (DAR) values

Antibody

  • Must be seen as a “carrier biomolecule”, with optimized biophysical and functional properties
  • High-to-good affinity for the target
  • Should promote efficient ADC internalization upon target binding
  • Long plasmatic circulation time (good pharmacokinetics and stability properties)

Linker

  • Plasma stable with no premature release of the cytotoxic payload into the bloodstream
  • Should ideally confers hydrophilic properties to improve pharmacokinetic properties and tolerability
  • Cleavable or non-cleavable linker, chosen according to the payload nature and the clinical indication
  • Cleavable linker paired with bystander payloads are generally used for solid tumors