Impact of Glycosylation on Effector Functions of Therapeutic

pharmaceutical

Les anticorps : mieux les connaître pour mieux s’en servir

L’utilisation thérapeutique des anticorps monoclonaux connaît une croissance exponentielle. Nos connaissances sur leur structure, en particulier celle des IgG1 largement utilisées en thérapeutique, se sont considérablement accrues. Cependant, de nombreux défis demeurent : l’amélioration de l’efficacité de ces molécules qui reste limitée, la diminution des risques d’événements indésirables chez les patients, et la mise au point de modèles précliniques adéquats, extrapolables à l’être humain. La sélection de cibles pertinentes par rapport à la pathologie visée et aux effets induits par l’anticorps est également un paramètre critique. Face à tous ces défis, la remarquable plasticité moléculaire des anticorps ainsi que les nouvelles possibilités d’ingénierie fondées sur des connaissances accrues de la structure et de la biologie des anticorps et de leurs cibles constituent autant d’espaces de recherche pour faire des anticorps monoclonaux des médicaments exceptionnels pour la santé humaine dans les prochaines années

Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response

Abstract The anti-CD20 monoclonal antibody (mAb) rituximab has been used successfully for lymphoma therapy for more than 10 years. Although several direct mechanisms by which anti-CD20 mAbs act have been characterized in vitro, their specific role in clinical efficacy is still debated. Little is known about the possible antitumor immune response that they may induce in patients, despite clinical data suggesting a “vaccinal” effect. We show here that an initial treatment with anti-CD20 induces protection against human CD20-expressing tumor cells and allows immunocompetent mice to survive tumor challenge. This long-lasting protection requires the presence of the Fc portion of the anti-CD20 mAb and is achieved through the induction of a cellular immune response. Only CD4+ cells were needed at the beginning of the treatment, but both CD4+ and CD8+ cells were required after tumor challenge to achieve protection. Finally, we show that interleukin-2 treatment, given after tumor challenge, improves the overall survival rate, compared with that obtained by anti-CD20 treatment alone. These findings demonstrate that anti-CD20 mAbs exert therapeutic effects through the induction of an adaptive cellular immune response, aside from any direct mechanisms involving effectors from innate immunity.</jats:p

Abstract 2921: Preclinical characteristics of NP137, a first-in-class monoclonal antibody directed against netrin-1 and inducing dependence receptors-mediated cell death

Abstract Background: Some receptors are active in the absence of ligand and actively trigger cell death through apoptosis. These receptors are called “dependence receptors” (DRs) as their expression at the cell surface renders cells critically dependent for their survival on ligand availability. Deleted in Colorectal Carcinoma (DCC) and UNC5H are prototypic DRs which induce apoptosis unless their ligand netrin-1 is present. It has been shown that netrin-1 is up-regulated in a large fraction of tumors and that interference with netrin-1/receptors interaction is associated with inhibition of tumor growth and metastasis in various preclinical models. We have generated the first humanized netrin-1 antibody, NP137, and characterized its antitumor activity. Preclinical results: NP137 is a humanized monoclonal IgG1 antibody, which binds netrin-1 in the nanomolar range affinity and efficiently inhibits the binding of netrin-1 to its receptor UNC5H2 (IC50: 0.5 nM). NP137 recognizes a netrin-1 specific epitope located in the second laminin-type EGF-like repeat. A crystal structure analysis shows that this region is crucial for the binding of netrin-1 to its receptor, providing a structural basis for the biological activity of NP137. In vitro, NP137 induced apoptosis in netrin-1-dependent cell lines as assessed by cell density measurement and caspase 3 activation. Ex vivo analysis performed on fresh human breast tumor slices (3D cultures) showed a specific and significant induction of apoptosis in tumor cells in approximately half of cases. In vivo, NP137 exhibited a significant anti-tumor effect associated with good pharmacokinetic properties in models of both solid tumors and hematologic malignancies. A dose-effect relationship was observed with an optimal pharmacologically active dose established at 10 mg/kg twice a week. We also showed that NP137 potentiates cancer cell death induced by cytotoxic drugs like doxorubicin or platinum derivatives as well as demethylating agents, which induce upregulation of netrin-1 and its receptors. In this context, a strong synergy with doxorubicin was shown in a rat syngeneic model of osteosarcoma, reversing its chemoresistant phenotype. Toxicological studies are ongoing with first results suggesting a high therapeutic margin. Conclusion: We are developing the first therapeutic antibody targeting netrin-1 and inducing dependence receptors-mediated tumor cell death. Preclinical results suggest a therapeutic potential both in solid tumors and hematological malignancies. A high therapeutic margin is expected, which may accelerate combination strategies. Based on these encouraging results, a first-in-human trial is planned at the end of 2015, with the support of EORTC. Note: This abstract was not presented at the meeting. Citation Format: Benjamen Ducarouge, Jean-Guy Delcros, Riad Abès, David Goldschneider, Benjamin Gibert, John Blachier, David Neves, Patrick Mehlen, Agnès Bernet, Stéphane Depil. Preclinical characteristics of NP137, a first-in-class monoclonal antibody directed against netrin-1 and inducing dependence receptors-mediated cell death. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2921. doi:10.1158/1538-7445.AM2015-2921</jats:p