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New Small Molecule Approaches in Immunotherapy

Posted on April 17th, 2017 by in Chemistry

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Therapeutic approaches based on small molecules have driven progress in the treatment of chronic diseases such as hypertension and lipid disorders for decades and advances are now being made in new areas such as rheumatoid arthritis and other autoimmune diseases as well as diseases mediated by protein-protein interactions: a largely untapped class of biological drug targets relevant to virtually all disease areas.

The advantage of medicines based on small molecules is that many are easy to use since they can be given orally and they are less expensive to manufacture. Their small size means they are also able to penetrate into cells, which means they can potentially reach a large number of target sites. As interest in medicines based on small molecules grows, new areas for their use are being investigated.

One of these new areas is immunotherapy. This is a rapidly evolving field based on harnessing components of the patient’s own immune system to counteract disease, either by delivering drugs with very high specificity or by eliciting sustained immune responses that effectively fight disease. Most of the breakthrough immunotherapeutics already in clinical use consist of monoclonal antibodies blocking T-cell checkpoint receptors or engineered T-cells targeted directly against tumor cells.

Although results using small molecules were not initially successful for immunotherapeutics, a growing number of preclinical and clinical studies are now under way. In particular, these are proving useful for the treatment of cancer.

The rapid progress in the understanding of the intracellular pathways involved in disease and immune reactions is aiding advancement in the development of small-molecule-based immune therapies, particularly in three areas:

  1. Identification of pathways and mechanisms of disease that can only or optimally be targeted by small molecules. Examples of these are: modulation of the immune response, trafficking to tumor microenvironments, and cellular infiltration. One of these novel mechanisms has been recently disclosed in a patent application by researchers from Genentech and Constellation Pharmaceuticals, describing the use of CBP/EP300 bromodomain inhibitors for cancer immunotherapy. Other small molecules under evaluation are inhibitors of USP7, a deubiquitylase implicated in several cancer signaling pathways, and IDO1 and TDO, two proteins that regulate T-cell response. At present, IDO1 is the only small molecule drug target evaluated in clinical trials.
  1. Development of new molecular classes such as small molecules that have the targeting and effector functions of antibodies. This would combine the advantages of both types of molecules. This is the case for a new class of molecules of intermediate size (approximately 7000 Da) created by a team from Yale University and Bristol-Myers Squibb called “synthetic antibody mimics targeting prostate cancer” (SyAM-Ps). These molecules can bind to prostate-specific membrane antigen and to Fc-gamma receptor I, promoting pro-inflammatory responses against prostate cancer cells. Innovative molecules like these open the path to the development of next-generation customizable immunotherapeutics.
  1. Design of combination treatments. A number of clinical studies have been initiated to evaluate combinations of small molecules drugs with modification of T-cells or checkpoint blocking antibodies.

The opportunities and cost benefits of small molecule approaches are likely to  result in an increased focus on these types of immunotherapies.


 

All opinions shared in this post are the author’s own.

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