Raymond J. Deshaies, Nature, 2020 reviewed recent development and outlook of multispecific drugs. Here are my key learnings.

A historical perspective of multispecific drugs

The author believes that multispecific drugs are the fourth generation of drugs, following the first wave of molecules with defined structure but undefined molecular target, defined molecules and molecular targets, and biologics. Though he also pointed out that many drugs that were developed work actually as multispecific drugs, with prominent example of Tacrolimus (which interact with both calcineurin and FKBP12), rapamycin (mTOR and FKBP12), Thalidomide (IKFZ1 and IKZF3 with CRBN). See more examples in Table 1.

Obligate multispecific drugs

Obligate (which means binding or biologically essential for survival) multispecific drugs work by engaging two or more entities so that either drug activity is limited at a specific location, or the target is brought into proximity to an endogenous effector that acts upon the target. They include sequentially binding obligate multispecific drugs (SOMs), concurrently binding obligate drugs that mediate localization (COMLs), and concurrently binding obligate multispecific drugs that function as matchmakers (COMMs).

  • SOMs engage two or more entities (dock and target) that are in different compartments. Examples of SOM include modified siRNA with ligands that bind the liver-restricted asialoglycoprotein receptor, and antibody-toxin complex.
  • In COML, the dock and the target reside in the same compartment. An example is an antibody-cytokine fusion. A COML must bind both the dock and the target simultaneously for the drug to work.
  • Matchmakers work by inducing proximity. They can enhance the therapeutic index (safety margin) by limiting its action to sites where the drug exerts its therapeutic effect. For instance degraders.

Matchmakers in focus

The author then introduced different types of matchmakers.

Small-molecule matchmakers include immunosuppressants, thalidomides, and proteolysis-targeting chimaeras such as Heterobifunctional proteolysis-targeting chimeric molecules (PROTACs), which contain a liganda that binds a target coupled to another ligand that binds an ubiquitin ligase, which can lead to the degradation of the target protein.

Biologic COMMs can link cell together, for instance bi-specific antibodies that bind to both T cell and cancer cells (bispecific CD3 engagers, BCE for short), or Emicizumab, a hetero-IgG that cross-links activated coagulation factor IX (known as FIXa) and factor X (FX). It substitutes the function of factor VIII (FVIII), which is missing in individuals with type-A haemophilia.

Future multispecific drugs

Future multispecific drugs may better localize drugs, for instance targeted delivery of oligonucleotides to organs other than liver, or delivery across the blood-brain barriers. Better bispecific CD3 engagers, for instance by adding a protease-sensitive linker, using a ‘AND&rsquo logic gate, or adopting a ‘cage-key’ system where a locked antibody can be only activated in the presence of a particular key.

Preclinical discovery and development of multispecific drugs is impeded by large screening space, physical chemical properties, PK and safety assessment, and lack of in vivo models. Beyond that, manufacture, stability, and dosing regiments also matter. The author argues for a tighter integration between biology, chemistry, engineering, and computer science in order to discovery and develop more multispecific drugs.

Conclusions

According to the author, about two thirds of the pipeline molecules through Phase I clinical trials at Amgen are multispecific drugs. Many academic research groups and companies are also working and investing in this area. It can be imagined that multispecific drugs will keep us busy in the coming years. Due to the many challenges above, I am confident that multiscale modelling and computational biology will be vital to understand their MoA and safety profiles with reduced or no use of animals.