Drug Discovery Today: Technologies最新文献

There is a great deal of excitement around the concept of targeting proteins for degradation as an alternative to conventional inhibitory small molecules and antibodies. Protein degradation can be undertaken by bifunctional molecules that bind the target for ubiquitin mediated degradation by complexing them with Cereblon (CRBN), von Hippel-Lindau or other E-3 ligases. Alternatively, E-3 ligase receptors such as CRBN or DCAF15 can also be used as a ‘template’ to bind IMiD or sulphonamide like compounds to degrade multiple context specific proteins by the selected E-3 ligases. The ‘template approach’ results in the degradation of neo-substrates, some of which would be difficult to drug using conventional approaches. The chemical properties necessary for drug discovery, the rules by which neo-substrates are selected by E-3 ligase receptors and defining the optimal components of the ubiquitin proteasome for protein degradation are still to be fully elucidate. Theis review will aim to critically evaluate the different approaches and principles emerging for targted protein degradation.

With Antibody-Drug Conjugate strategies firmly focussed on the precise conjugation to the large protein Immunoglobulin-G format, it is easy to miss the more recent technological innovations in small-format drug conjugates. Here, the targeting ligand can be at 50–95% reduced in size, or even smaller if peptidic in nature. Antibody domains or alternative binding scaffolds, chemically-modified with ultra-potent cytotoxic payloads offer an alternative approach for oncology therapeutics, promising a wider therapeutic window by virtue of superior solid tumour penetration properties and more rapid system clearance. Many of the traditional ADC concepts still apply, but as these miniaturised ADCs enter the clinic over the next 2–3 years, we will learn whether these new features translate to patient benefits.

Bispecific antibodies (BsAbs) are antibodies with two different paratopes. In the past decade, advances in protein engineering have enabled the development of more than 100 formats of BsAbs. With two BsAbs approved for therapeutic use and more than 60 in clinical trials, this research area has shifted from being effervescent to being a mainstream therapeutic development topic. In parallel, recent progress in protein conjugation and cytotoxicity of small molecule drugs has resulted in a boom in monospecific antibody therapeutics development such as antibody–drug conjugates (ADCs). Recent examples have demonstrated how BsAbs approaches can be used to generate ADCs with better efficacy and safety profile. Rather than examining these two different yet similar areas independently, this minireview will explore the potential synergies that can exist between them.

Antibody conjugated nanoparticles (ACNPs) represent a novel strategy for the development of therapies exploiting antibodies to augment the delivery of chemotherapy payloads. Following in the footsteps of the success of antibody drug conjugates (ADCs), ACNPs are only now reaching clinical evaluation. In this review we discuss the success of ADCs and explore the opportunities ACNPs offer, such as broad chemotherapy payload selection, high drug to antibody ratios and the ability to finely tailor drug release in comparison to ADCs. The ability of ACNPs to elicit increased avidity due to multivalent effects and the potential to use these modular platforms in immunotherapeutic approaches is also explored. Through addressing challenges that still remain in bringing these complex formulations to the clinic, ACNPs hold obvious potential for the treatment of a wide range of cancers and other diseases where selective targeting of drug agents is essential.

Antibody-drug conjugates (ADCs) consist of monoclonal antibodies (mAbs) or antibody fragments conjugated to biologically active molecules (usually highly cytotoxic small molecules) through chemical linkers. Although no ADCs containing covalent-binding DNA-interactive payloads have yet been approved (although two containing the DNA-cleaving payload calicheamicin have), of those in clinical trials systemic toxicities are beginning to emerge. This article discusses the observed toxicities in relation to the structures and mechanisms of action of payload type.

Antibodies and their derivatives radiolabelled with positron- and gamma-emitting radiometals enable sensitive and quantitative molecular Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging of antibody distribution in vivo. Chelators that are covalently attached to antibodies allow radiolabelling with metallic PET and SPECT radioisotopes. Conventional strategies for chelator-protein conjugation generate heterogeneous mixtures of bioconjugates that can exhibit reduced affinity for their receptor targets, and undesirable biodistribution and pharmacokinetics. Recent advances in bioconjugation technology enable site-specific modification to generate well-defined constructs with superior properties. Herein we survey existing site-specific chelator-protein conjugation methods. These include chelator attachment to cysteines/disulfide bonds or the glycan region of the antibody, enzyme-mediated chelator conjugation, and incorporation of sequences of amino acids that chelate the radiometal. Such technology will allow better use of PET and SPECT imaging in the development of antibody-based therapies.

The antibody-drug conjugate (ADC) field has seen a remarkable expansion in the number of entrants in clinical studies. Many of these agents employ newer conjugation technologies that have been developed over the last decade that confer various attributes to the ADCs prepared with them, including stability, potency, and homogeneity. In many cases, these new ADCs appear demonstrably superior to earlier technologies in preclinical models of activity and toxicology, but the degree to which these improvements will translate to the clinic is only starting to be seen. Many of these technologies are now competing head-to-head by targeting the same antigen in similar patient populations, allowing for a direct comparison of their clinical performance properties. As lessons from these experiences feed back into discovery research, future iterations of ADC design may be expected to bring improved therapeutics into the clinic.

Bioconjugation, the modification of biological macromolecules such as proteins, is an up and coming area in the field of chemical biology. Antibody-drug conjugates (ADCs), combining the antigen-selectivity of natural antibodies with the cytotoxic potency of small molecule drugs, are a powerful therapeutic technology. Four such constructs are currently on the market for cancer therapy. However, the conjugation methodology employed in these therapeutics is far from ideal. Herein we provide an overview on methods that attempt to increase the safety and efficacy of ADCs via “self-hydrolysing maleimides” or by improving the stability of maleimide-conjugates by other means. We find that some very promising reagents have been reported, however the mechanism by which each of these reagents acts is not clear, thus limiting rational design for some strategies.

The field of targeted therapeutics has benefitted immeasurably from the development of high-affinity antibodies. These important ligands have facilitated the development of effective therapies, particularly when conjugated to potent cytotoxic payloads i.e. in antibody–drug conjugates (ADCs). The success of ADCs is evidenced by rapid adoption within the pharmaceuticals community; many major companies have dedicated ADC research programmes. However, despite the advantages, the field of ADCs has failed to live up to its full potential. Studies have emerged suggesting that traditional IgG scaffolds may not be the optimal format for targeted payload delivery. In response, the protein engineering community has begun to explore alternative high-binding protein scaffolds as antibody mimics. In this short review I will summarise the generation, modification, and application of emerging antibody fragments and synthetic antibody mimics, with a focus on their use as drug carriers. The review aims to highlight the advantages of antibody mimics, and how they could be employed to overcome the issues and limitations of traditional ADCs.