Philochem AG | Date: 2016-08-02
A targeted therapeutic agent comprising a compound of formula I: B-L-D(I), wherein: B is a low molecular weight binding moiety for Carbonic Anhydrase IX (CAIX); D is a drug moiety; and L is a linker group that undergoes cleavage in vivo for releasing said drug moiety in an active form. The drug moiety is suitably a cytotoxic agent for targeted delivery to cancer cells expressing CAIX. The binding moiety B suitably comprises a sulfonamidothiadiazole moiety. The binding moiety B may comprise one, two or more groups capable of binding to CAIX. The linker group suitably comprises a disulfide bond and/or a triazole group and/or a cleavable peptide group.
Philochem AG | Date: 2016-08-03
A targeted therapeutic agent comprising a compound of formula: B-L-D wherein: B is a non-internalizing binding moiety specific for a cancer associated protein; D is a cytotoxic drug moiety; and L is a linker group that undergoes cleavage in vivo for releasing said drug moiety in an active form. The binding moiety is a ligand for the cancer associated protein whereby drawbacks associated with the use of internalizing ligands are avoided.
Philochem Ag | Date: 2015-03-06
This invention relates to the purification of nucleic acid conjugates, for example for use in DNA encoded chemical libraries. Reaction members that comprise nucleic acid conjugate reaction products and nucleic acid or nucleic acid conjugate reactants comprising a first reactive group are contacted with a capping molecule comprising a capture group. The capping molecule reacts with the first reactive group to form a covalent bond, thereby attaching the capture group to nucleic acid or nucleic acid conjugate reactants in reaction members. The nucleic acid or nucleic acid conjugate reactants are then removed from the reaction members using a binding member that binds the capture group, thereby producing a purified population of nucleic acid conjugate products. Methods of producing purified populations of nucleic acid conjugate products and nucleic acid chemical libraries are provided along with chemical libraries and kits.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2012.2.1.1-1-B | Award Amount: 15.82M | Year: 2012
EURenOmics will integrate several established consortia devoted to rare kidney diseases with eminent need and potential for diagnostic and therapeutic progress (i.e. steroid resistant nephrotic syndrome, membranous nephropathy, tubulopathies, complement disorders such a haemolytic uraemic syndrome, and congenital kidney malformations). The Consortium has access to the largest clinical cohorts assembled to date (collectively >10,000 patients) with detailed phenotypic information and comprehensive biorepositories containing DNA, blood, urine, amniotic fluid and kidney tissue. The project aims to (1) identify the genetic and epigenetic causes and modifiers of disease and their molecular pathways; (2) define a novel mechanistic disease ontology beyond phenotypical or morphological description; (3) develop innovative technologies allowing rapid diagnostic testing; (4) discover and validate biomarkers of disease activity, prognosis and treatment responses; and (5) develop in vitro and in vivo disease models and apply high-throughput compound library screening. For these purposes we will integrate comprehensive data sets from next generation exome and whole-genome sequencing, ChiP-sequencing, tissue transcriptome and antigen/epitope profiling, and miRNome, proteome/peptidome, and metabolome screening in different body fluids within and across conventional diagnostic categories. These data will be combined in a systems biology approach with high-resolution clinical phenotyping and findings obtained with a large array of established and novel in vitro, ex vivo and in vivo disease models (functiomics) to identify disease-associated genetic variants involved in monogenic or complex genetic transmission, disease-defining molecular signatures, and potential targets for therapeutic intervention. These efforts will converge in the development of innovative diagnostic tools and biomarkers and efficient screening strategies for novel therapeutic agents.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.1.2-1 | Award Amount: 3.88M | Year: 2012
Therapeutic antibodies are the largest and fastest growing class of pharmaceutical biotechnology products, with annual sales above 30 billion US$. In some cases, antibody products have revolutionized the management of patients, e.g. TNF-blocking antibodies in Arthritis or Rituxan in lymphoma. However, for most antibody therapies, only a subset of patients benefit from treatment. Thus, there is an urgent need to develop more potent therapeutic antibodies and to understand the molecular basis for the differential responses of patients to treatment. This consortium consists of European centres of excellence being pioneers in the field of therapeutic antibody development and (pre-) clinical studies and will tackle both of these challenges: Innovative immunocytokines L19-IL2 and F8-IL10 are developed by Philogen for the treatment of metastatic melanoma and rheumatoid arthritis respectively at multiple clinical centres including Graz and Tbingen. Building on the strong background in proteomics biomarker discovery of ETH Zurich and Philochem, an innovative methodology (HLA-peptidome analysis) will be utilized for gaining information on the immune response in animal models and patients which receive antibody treatments. This method is based on the observation that HLA molecules in complex with peptides can be detected in the patient blood and that hundreds of HLA-associated peptides can be sequenced by mass spectrometry. The technology will be used for the profiling of responses following antibody treatment for patients with cancer and rheumatoid arthritis, as well as animal models of transplant rejection. This systems biology approach has the potential to revolutionize patient stratification in very short time. Finally, patient selection strategies will be investigated using the clinical-grade immunocytokine (F8-IL10) as an example, monitoring antibody uptake at the site of disease by immuno-PET imaging methodologies at VUMC Amsterdam in collaboration with Philogen.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-1.4-1 | Award Amount: 7.86M | Year: 2008
Cancer is the second leading cause of death in European countries, and one of the most imminent health problems in the developed world. Innovative, so-called targeted therapies are urgently needed that aim specifically at cancer cells or to cells of the stroma that support tumor growth. The ultimate goal of a targeted therapy is to increase anti-tumor efficacy with lowest possible side effects. Rapid and efficient translation of basic scientific advances into reagents, and targeted molecular leads for preclinical and clinical research and development based on scientific rationales and state-of-the-art technologies, optimally requires an interdisciplinary, collaborative, team-oriented approach. EUCAAD represents a virtual research institute in Europe and consists of 9 research participants including 4 SMEs devoted to the discovery and evaluation of new antibodies for therapy of human cancers. The consortium consists of researchers from SMEs and scientific and clinical centres that have gained international acclaim in this area of research, many of who have worked together in previous EU funded applications e.g. ANGIOSTOP, EUCAPS, ESTDAB and ENACT. Within the consortium there is unique expertise regarding target discovery, target validation, antibody production and initiation of clinical trials. As part of its efforts to translate laboratory research into viable cancer therapies the individual partners has accumulated an extensive portfolio of intellectual property providing a competitive edge to this application. The focus of the grant is the development and evaluation of antibodies against new target structures on tumour cells and blood vessels supplying tumours which are responsible for tumour angiogenesis, progression and metastasis. Collectively, the activities of this consortium can improve the cancer treatment standards in Europe and provide economic benefit to European biotechnology and pharmaceutical research by providing novel immunopharmaceuticals.
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH-2007-2.4.1-7 | Award Amount: 3.92M | Year: 2008
The selective delivery of bioactive agents (cytotoxics, radionuclides, cytokines) at the tumor site, while sparing normal tissues, represents one of the most promising avenues for the development of anticancer therapies with unprecedented efficacy and tolerability. Monoclonal antibodies represent the preferred vehicle for the targeted delivery of bioactive agents to cancer sites, as they can display a preferential accumulation in primary and metastatic tumor lesions already few hours after intravenous administration. Certain monoclonal antibody derivatives can remain on the neoplastic mass for several days, thus enabling the slow release of potent cytotoxics or the continuous action of bioactive agents such as cytokines or therapeutic radionuclides. The ADAMANT Project aims at the generation of anticancer agents of superior quality, which rely on the antibody-based delivery of cytotoxics, radionuclides or immunostimulatory cytokines to either vascular tumor antigens or to tumor cell membranes. While clinically-validated antibodies will allow the rapid development of therapeutic strategies based on novel antibody derivatives, innovative perfusion-based chemical proteomic technologies will facilitate the discovery of accessible and abundant tumor-associated antigens, ideally suited for the targeted delivery of bioactive agents to cancer sites. Imaging methodologies will guide us in the selection of antigens, antibodies and therapeutic agents with optimal pharmacokinetis and pharmacodynamics. Finally, therapy studies in tumor-bearing mice, featuring the use of antibody-derivatives in combination with other anti-cancer drugs (cytotoxic, biological, vascular disrupting agents) will provide insights about how to best translate the results of the ADAMANT Project to clinical development. The Project will be truly successful if at least one antibody-based tumor targeting agent enters full-blown industrial development programs by the end of the ADAMANT Project.
Gutbrodt K.L.,ETH Zurich |
Casi G.,Philochem AG |
Neri D.,ETH Zurich
Molecular Cancer Therapeutics | Year: 2014
Antibody-drug conjugates are increasingly being used for cancer therapy, but little is known about their ability to promote anticancer immunity, which may lead to long-lasting remissions. We investigated the therapeutic effect of antibody-based pharmacodelivery of cemadotin, a cytotoxic drug, and IL2, a strong proinflammatory cytokine. Using the F8 antibody, which selectively localizes to the tumor neovasculature, combination treatment led to tumor eradication, in a process dependent on CD8+ T cells and natural killer cells in the C1498 syngeneic mouse model of acute myelogenous leukemia. The clinical combination of antibody-drug conjugates and antibody-cytokine proteins should be facilitated by their orthogonal toxicity profiles. ©2014 AACR.
Casi G.,Philochem AG |
Neri D.,ETH Zurich
Journal of Medicinal Chemistry | Year: 2015
Conventional cancer chemotherapy heavily relies on the use of cytotoxic agents, which typically do not preferentially localize at the tumor site and cause toxicity to normal organs, preventing dose escalation to therapeutically active regimens. In principle, antibodies and other ligands could be used for the selective pharmacodelivery of cytotoxic agents to the neoplastic mass. For many years, the availability of ligands, capable of selective internalization into tumor cells, has been considered to be an essential requirement for the development of targeted cytotoxics. This assumption, however, has recently been challenged on the basis of therapeutic data obtained with noninternalizing drug conjugates. Moreover, quantitative evaluations of the tumor targeting properties of antibodies and of small organic ligands have provided new insights for the implementation of optimal strategies for the development of targeted cytotoxics. In this article, we highlight opportunities and challenges associated with the clinical and industrial development of antibody-drug conjugates and small molecule-drug conjugates for cancer therapy. © 2015 American Chemical Society.
Philochem Ag | Date: 2014-12-11
This invention relates to the synthesis of nucleic acid-encoded chemical libraries using common adaptor sequences. Nucleic acid strands coupled to chemical moieties may be contacted with identifier oligonucleotides comprising coding sequences encoding the chemical moieties and an adaptor oligonucleotides, such that the adaptor oligonucleotide hybridizes to both the nucleic acid strands and the identifier oligonucleotides to allow ligation of the identifier oligonucleotides to the nucleic acid strands. The adaptor oligonucleotide is then removed. Nucleic acid-encoded chemical libraries, and methods of producing or screening such libraries are provided.