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Otelfingen, Switzerland

Krall N.,ETH Zurich | Pretto F.,Philochem AG | Neri D.,ETH Zurich
Chemical Science | Year: 2014

There is a pressing need for the development of innovative chemical drug delivery strategies in oncology, since conventional chemotherapeutic agents typically do not localise to solid tumours in vivo. It is widely accepted that bivalent antibody formats accumulate in tumours more strongly than monovalent ones and that they should thus be preferred for antibody-based pharmacodelivery approaches. For small molecule-drug conjugates this is less clear. Here, we show that a bivalent ligand against the tumour marker carbonic anhydrase IX leads to an improved tumour-targeting performance compared with the corresponding monovalent counterpart in the SKRC52 model of constitutively CAIX-positive renal cell carcinoma. A bivalent disulfide-linked small drug conjugate with the potent cytotoxic maytansinoid DM1 as the payload can mediate complete eradication of the same tumours, which are resistant to standard-of-care therapeutics, in a proportion of treated mice. In the A375 melanoma model, which preferentially expresses CAIX at sites distant to blood vessels, no measurable tumour accumulation could be observed. Our results suggest that the use of bivalent small molecule ligand-drug conjugates against CAIX may represent an attractive chemical strategy for the treatment of constitutively CAIX-positive kidney cancer. © 2014 the Partner Organisations. Source

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. Source

Pretto F.,Philochem AG | Elia G.,Philochem AG | Castioni N.,ETH Zurich | Neri D.,ETH Zurich
Cancer Immunology, Immunotherapy | Year: 2014

Antibody-cytokine fusion proteins ("immunocytokines") represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8-IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8-IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4+ T cells 24 h after the administration of the combination. The fusion proteins F8-IL2 and L19-IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients. © 2014 Springer-Verlag. Source

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. Source

List T.,ETH Zurich | Casi G.,Philochem AG | Neri D.,ETH Zurich
Molecular Cancer Therapeutics | Year: 2014

The combination of immunostimulatory agents with cytotoxic drugs is emerging as a promising approach for potentially curative tumor therapy, but advances in this field are hindered by the requirement of testing individual combination partners as single agents in dedicated clinical studies, often with suboptimal efficacy. Here, we describe for the first time a novel multipayload class of targeted drugs, the immunocytokine-drug conjugates (IDC), which combine a tumor-homing antibody, a cytotoxic drug, and a proinflammatory cytokine in the same molecular entity. In particular, the IL2 cytokine and the disulfide-linked maytansinoid DM1 microtubular inhibitor could be coupled to the F8 antibody, directed against the alternatively spliced EDA domain of fibronectin, in a site-specific manner, yielding a chemically defined product with selective tumor-homing performance and potent anticancer activity in vivo, as tested in two different immunocompetent mouse models. ©2014 AACR. Source

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