Targeting with specific antibodies

Antibody-Drug Conjugates (ADCs) represent an innovative therapeutic application combining the favourable selectivity, stability and pharmacokinetic profiles of monoclonal antibodies with the potent antitumor activityof highly cytotoxic small-molecule drugs. Unlike traditional chemotherapy, ADCs are designed to target and kill only the cancerous cells while sparing healthy tissues.

Today, researchers all over the world keep on finding and characterizing more and more specific tumor markers. These markers allow us not only to identify and diagnose the corresponding types of cancers they are specific to, but also to discriminate cancer cells among healthy ones in their vicinity. Traditional chemotherapy protocols rely on drug’s formulation and pharmacokinetics. By contrast, ADC-driven treatments can target specifically an extracellular marker. This feature limits drastically their impact on healthy tissues, which leads to a better treatment’s effectiveness and tolerance by the patients.

Killing cancer with efficient cytotoxic drugs

Once an ADC is bound to its specific extracellular antigen target, the cancer cell internalizes the molecule by endocytosis. The resulting early endosome is then driven through the microtubule tracks and ultimately fuses with lysosome once next to the perinuclear space. Proteolytic enzymes perform degradation of the ADC-Marker couple, including the antibody and the linker, which subsequently releases the potent drug payload. The drug can then diffuse throughout the cell and exert its cytotoxic activity.

Most of the highly-potent cytotoxic drugs used in the ADC field are DNA damaging agents (such as pyrrolobenzodiazepine or « PBDs ») or microtubules inhibitors (such as maytansinoids or auristatins).
To overcome resistance to these current payloads in the clinic, there is a need for new compounds having differentiated innovative mechanisms of action. As an example were introduced in the recent years DNA or RNA topoisomerase inhibitors (PNU-159682, α-amanitin), spliceosome inhibitors (thailanstatins) or kinesin splindle protein (KSP) inhibitors.

Decreasing the doses

Thanks to the specificity of monoclonal antibodies for their antigens, the required doses of bioactive molecules are significantly decreased. There is indeed no need anymore to overload the bloodstream anymore since a higher fraction of molecules will reach their target accurately. Furthermore, this limits even more the adverse effects the drug can have on healthy tissues. The endocytose mechanism also allows better entry of cytotoxic drugs within the cancer cells than passive or even transporter-mediated entry of the drug alone. Endocytosis allows to not be dependent on drug’s polarity and local concentration to cross the lipid membrane through specific transport channels.

Today the challenge lies in developing linkers with two apparently opposite features:

  • resistance to physiological and physicochemical constraintes of the patient’s organism,
  • sensibility to proteolytic enzymes of lysosomes to release the payload.

That’s why our core business relies on our exclusive antibody-drug conjugation technology, and why we are able to offer you a new innovative coupling service.

Improving the therapeutic index of ADCs

As a targeted therapy, ADCs deliver therapeutic compounds in a manner that improves the therapeutic window. As a result, ADC therapies are expected to be more efficient and better tolerated in the clinic. Innovations in the field of research aims to further improve the therapeutic index of ADCs by:
  • improving the drug-linker design (improved plasma stability, use of enzyme-cleavable moiety ar lack thereof, use of new payloads with new mechanisms of action, improved payload protection against metabolism.
  • improving ADC physicochemical and pharmacological parameters (improved drug-loading, increased overall hydrophilicity, improved pharmacokinetics, decreased non-specific uptake).
  • improving the antibody component (new tumor targets, bispecific antibodies boosting the endocytosis step, Fc region removal to reduce non-specific interactions) or using an antibody mimetic as targeting unit (nanobodies, therabodies, affibodies…

Our solution: our ADC platform

Our drug-linker technology aims to address all these considerations by delivering ADCs that:

  • have an increased drug loading capacity (DAR of 8-16) without negative impact on aggregation and/or pharmacokinetics,
  • are homogeneous and plasma-stable,
  • have improved hydrophilicity and pharmacokinetics profiles,
  • are easier to develop and produce since our technology is directly applicable to any monoclonal antibody with no re-engineering required nor tedious enzymatic coupling procedures.

Our platform is modular and readily applicable to any conventional or next-generation toxic payload. The platform can be paired with enzyme-cleavable moieties (Val-Cit, Val-Ala, glucoronide triggers…) or can be used in non-cleavable linker designs (when the final proteolytic degradation of the ADC is predominantly held responsible for the release of the toxic payload).

Because of the increased hydrophilicity conferred to the drug-linker, our technology is applicable to the antibody-grafting of very hydrophobic payloads known for their aggregation propensity or difficult bioconjugation procedures.

See our innovative ADC coupling services for more information.