Kinases are one of the most important drug target classes in several therapeutic areas, and particularly in Oncology, with >40 drugs already approved for a wide variety of solid tumors and leukemias, and an impressive number of molecules in clinical development. Despite exponential progress in the last 15 years, it is commonly recognized that the full potential of kinase pharmacological inhibition is still to be harvested, as more knowledge is generated on the physiological and pathological role of the 500+ components of this family of enzymes.
The Kinase Platform at Nerviano Medical Sciences
Pioneering the early recognition of the relevance of kinases for personalized anticancer therapy, Nerviano Medical Sciences has developed a dedicated infrastructure, called the Kinase Platform, to leverage kinase-targeted chemistry and biology investments across multiple targets of this family.
The platform is founded on the Kinase-Targeted Library (KTL), a proprietary collection of about 100,000 molecules designed to interact with kinases and other purine-binding enzymes, with a strong IP broadly covering the kinase inhibitors chemical space. The KTL library has been tested against multiple kinase targets over time, proving to be an optimal starting point for hit identification and initial SAR generation. The library is incrementally expanded over time with the support of crystallography and modeling approaches, which are also applied to improve the Hit affinity and selectivity for specific targets. This chemical asset is complemented by a broad panel of biochemical assays, including the Kinase Selectivity Screening (KSS), a panel of >100 automated biochemical kinase assays, and several cellular assays that allow us to rapidly and efficiently generate the biochemical and pharmacological profiles of the Hit and Lead compounds. We have also assembled a collection of potent inhibitors designed to probe the different kinome members and use this compound set in cellular assays for new target identification and drug repositioning in disease-specific contexts.
Leveraging the Kinase Platform
The kinase platform has already delivered potent and selective kinase inhibitors that are currently in clinical development, followed by several advanced preclinical projects. In order to continue to harvest the therapeutic potential of the kinase family, we apply different approaches for the identification and validation of novel targets, from large scale genomic and bioinformatics based kinase expression data and mutation analysis to kinome-wide siRNA screenings in different tumor cell lines.
We are committed to continue capitalizing upon our well proven knowledge and expertise in kinase chemistry and biology for the rapid and efficient advancement of a broad portfolio of preclinical and clinical kinase inhibitor programs in key areas of interest in Oncology and Oncoimmunology.
The ADC Payload Platform
ADCs, or Antibody-Drug Conjugates, are extremely potent and selective biopharmaceutical drugs designed to specifically target cancer cells. ADCs typically consist of a monoclonal antibody that binds specifically to an antigen which is highly expressed on tumor tissue, conjugated (or chemically “linked”) to a highly cytotoxic drug. In of themselves, these two components would have little specific effect activity against tumors, since without the cytotoxin, the antibody would simply bind to the tumor cell surface with little or no biological consequence, while the cytotoxin by itself would circulate randomly around the body, damaging normal as well as tumor cells along its path. Instead, the judicious combination of these two types of agent can yield an ADC, with the combined properties of being able both to specifically bind tumor cells (via the monoclonal antibody) and to effectively kill them (via the cytotoxin). Ideally, when an ADC binds to its target on the cancer cell surface, it is internalised within the tumor and only then is the activity of the cytotoxin drug fully unleashed.
The challenges of making a fully functional ADC
Because of the chemical and biological complexity inherent in developing ADCs as drugs (for example, the properties of the native antibody must be fully maintained in the ADC and the cytotoxin must be able to be efficiently released only when required, i.e. only within targeted cells), two crucial factors in the process of producing a new ADC from a candidate monoclonal antibody are the choice of the cytotoxic drug and the chemical linkage between the antibody and the drug: – it is here where Nerviano Medical Sciences excels.
Nerviano Medical Sciences’s edge in ADC technology
Thanks to our strong heritage in the field of cytotoxin chemistry Nerviano Medical Sciences was the headquarters of Farmitalia-Carlo Erba, the Italian pharmaceutical company that first discovered and developed anthracycline cytototoxin for tumor therapy), we have identified a number of novel ADC payloads. The most advanced amongst these is an innovative, thienoindole-based class of DNA minor groove binding agents (MGBs) that possesses cellular activity profiles and physicochemical properties that are particularly suited to antibody conjugation. These thienoindoles MGBs have a distinct, very different cytotoxic mechanism and >10X greater cellular activity compared with the tubulin-active agents most often utilised to date for ADC generation. All this while maintaining high versatility for antibody conjugation.
NMS-P945 is NMS’s lead Antibody Payload. NMS-P945 contains the highly active thienoindole NMS-P528 and a thiol-reactive moiety which readily allows direct coupling to monoclonal antibodies. NMS-P945 typically yields a DAR (drug-antibody ratio) of around 4, with low side-generation of DAR 0 or DAR 8 species and with negligible induction of protein aggregation, thus simplifying the subsequent purification steps. NMS-P945 also comprises a protease-cleavable linker, which directs intracellular release of the active MGB species, NMS-P528.