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Function – mode of action

Better knowledge of drug function increases the likelihood of producing safe and more effective drugs. What limits a drug’s potential for success is either lack of safety (early clinical trials) or lack of therapeutic effect (later clinical trials). The more you know about the function of your drug, the more likely you are to have a successful clinical trial and establish your drug as a profit-making standard treatment.

Mode of action of immune inhibitor drugs

Many drugs inhibit the immune system. This can be studied by introducing a broad stimulus (e.g. a low dose of LPS) or a target-specific stimulus (e.g. an agonistic T cell specific antibody) and observing whether the drug inhibits the immune activation of that stimulus. The variety of readouts can be included to characterize the immune profile for the inhibitory response such as: cellular activation, cytokine release, complement activation etc.

Mode of action of therapeutic monoclonal antibodies (mAbs)

Antibodies produce a therapeutic effect by binding target cells, which has a net effect that may be antagonistic, agonistic, blocking or cell-depleting. When a target cell is bound by a monoclonal antibody, two mechanisms can lead to the cell’s death: antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). Our platform allows these mechanisms to be studied simultaneously, which is unique in preclinical testing. The responsible killing mechanism can thus be identified for antibodies known to result in target cell death, simply by specifically blocking one mechanism or the other. The activation profile of the effector cells can be combined with viability monitoring of the target cells

Antibodies can induce two major mechanisms that lead to target cell death: antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). ADCC is induced when the target-bound antibody is recognized by FcγRs on effector cells that cause cell lysis of the target cell (left). CDC is induced when the target-bound antibody is recognized by C1q, causing a cascade of events that result in the release of soluble C3a and C5a and the formation of the membrane attack complex (MAC) that lyses the target cell (right).

Testing methods & capabilities

  • CDC complement activation: C3a and C5a.
  • ADCC by detection of NK cell activation: surface CD69 and CD107a, or intracellular IFNg/TNFa.
  • Target cell viability: flow cytometry/hematology parameters.
  • CDC/ADCC functional assessment: performed by blocking ADCC (CD16 block) and CDC (C1q, C3, C5 block) and looking at the effects of the parameters described above.

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