The role of small molecules in cell and gene therapy.

Cell and gene therapies have achieved impressive results in the treatment of rare genetic diseases using gene corrected stem cells and haematological cancers using chimeric antigen receptor T cells. However, these two fields face significant challenges such as demonstrating long-term efficacy and safety, and achieving cost-effective, scalable manufacturing processes. The use of small molecules is a key approach to overcome these barriers and can benefit cell and gene therapies at multiple stages of their lifecycle. For example, small molecules can be used to optimise viral vector production during manufacturing or used in the clinic to enhance the resistance of T cell therapies to the immunosuppressive tumour microenvironment. Here, we review current uses of small molecules in cell and gene therapy and highlight opportunities for medicinal chemists to further consolidate the success of cell and gene therapies.

The Landscape of Early Clinical Gene Therapies outside of Oncology.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.e., strategies that modify an individual's protein make-up by introducing exogenous nucleic acid or nucleic acid modifiers, regardless of delivery. Unmodified cell therapies, oncology therapies (reviewed elsewhere), and vaccine programs (distinct therapeutic strategy) were not included. Using a December 31, 2018 cutoff date, we identified 336 gene therapies being developed for 138 different indications covering 165 genetic targets. In all, we found that the early clinical GT landscape comprises a very disparate group of drug candidates in terms of indications, organizations, and delivery methods. We also highlight interesting trends, revealing the evolution of the field toward in vivo therapies and adeno-associated virus vector-based delivery systems. It will be interesting to witness what proportion of this current list effectively translates into new medicines.

Current Status of Gene Engineering Cell Therapeutics.

Ex vivo manipulations of autologous patient's cells or gene-engineered cell therapeutics have allowed the development of cell and gene therapy approaches to treat otherwise incurable diseases. These modalities of personalized medicine have already shown great promises including product commercialization for some rare diseases. The transfer of a chimeric antigen receptor or T cell receptor genes into autologous T cells has led to very promising outcomes for some cancers, and particularly for hematological malignancies. In addition, gene-engineered cell therapeutics are also being explored to induce tolerance and regulate inflammation. Here, we review the latest gene-engineered cell therapeutic approaches being currently explored to induce an efficient immune response against cancer cells or viruses by engineering T cells, natural killer cells, gamma delta T cells, or cytokine-induced killer cells and to modulate inflammation using regulatory T cells.

Anti-serum albumin domain antibodies in the development of highly potent, efficacious and long-acting interferon.

Serum albumin-binding domain antibodies (AlbudAbs) have previously been shown to greatly extend the serum half-life of the interleukin-1 receptor antagonist IL-1ra. We have subsequently extended this approach to look at the in vitro activity, in vivo efficacy and pharmacokinetics of an agonist molecule, interferon (IFN)-alpha2b, fused to an AlbudAb. Here we describe this molecule and show that in this format AlbudAb half-life extension technology displays significant advantages in comparison with other methods of half-life extension, in particular genetic fusion to serum albumin. When compared directly IFN-alpha2b fused to an Albudab shows higher potency, increased serum half-life and greater efficacy than human serum albumin fused to IFN-alpha2b. AlbudAbs are therefore an ideal platform technology for creation of therapeutics with agonist activity and long serum half-lives.

A technology platform for the fast production of monoclonal recombinant antibodies against plant proteins and peptides.

The application of recombinant antibodies in plant biology research is limited because plant researchers have minimal access to high-quality phage display libraries. Therefore, we constructed a library of 1.3 x 10(10) clones displaying human single-chain variable fragments (scFvs) that is available to the academic community. The scFvs selected from the library against a diverse set of plant proteins showed moderate to high antigen-binding affinity together with high specificity. Moreover, to optimize an scFv as immunodetection agent, two expression systems that allow efficient production and purification of bivalent scFv-Fc and scFv-CkappaZIP fusion proteins were integrated. We are convinced that this antibody platform will further stimulate applications of recombinant antibodies such as the diagnostic detection or immunomodulation of specific antigens in plants.