Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013

Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure–function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose–response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar

A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics - a European industry perspective

There is much debate in the pharmaceutical industry on how to translate the current guidelines on immunogenicity testing for biotherapeutics into a testing strategy that suits the specific requirements of individual drug candidates. In this paper, member companies from the European immunogenicity platform (EIP) present a consensus view on the essential requirements for immunogenicity testing of a biotherapeutic throughout the various phases of drug development, to ensure patient safety and to enable successful market entry. Our aim is to open the debate and provoke discussion on this important topic which is unique to biotherapeutic drug development. The scope of this paper is limited to aspects relevant to biotherapeutic drug development and does not include fundamental academic studies of immunogenicity. Here, we propose two pre-defined testing strategies for the detection and characterization of anti-drug antibody (ADA) responses where the different strategies are based on the phase of development for a biotherapeutic, a. without (category 1) and b. with (category 2) the expected potential to elicit ADA mediated severe clinical consequences. The harm of a potential ADA response determines which of the two testing strategies is adopted. The scientific rationale on which the "case-by-case" approach advocated in white papers and guidance documents may be translated for each individual drug development program is provided and, underpins the recommendations made here

T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia

Immunogenicity of biotherapeutics and the elicitation of anti-drug antibodies (ADA) are a key concern for their efficacy, pharmacokinetics and safety. Prediction of clinical immunogenicity on the basis of quality attributes of biopharmaceuticals or by utilizing preclinical in vitro and in vivo screening remains challenging. Even fully human biotherapeutics have the potential for immunogenicity, and one important factor that might enhance potential immunogenicity is protein aggregation. A particularly severe consequence of immunogenicity of a biotherapeutic is the rare development of antibody-mediated pure red cell aplasia (PRCA) in anemic patients treated with aggregated forms of recombinant human erythropoietin (rhEPO). Here, we investigated in vitro T cell responses to (i) heat-induced rhEPO aggregates, (ii) tungsten-induced rhEPO aggregates in clinical lots associated with rhEPO-neutralizing antibodies and PRCA, and (iii) ex vivo T cell recall responses of patients treated with rhEPO without PRCA, and of a patient who developed PRCA after treatment with a clinical batch with elevated levels of tungsten and aggregates. To our knowledge, this is the first time that T cell assays confirm the root cause of increased rhEPO immunogenicity associated with PRCA

Focus topics for the ECFA study on Higgs / Top / EW factories

International audienceIn order to stimulate new engagement and trigger some concrete studies in areas where further work would be beneficial towards fully understanding the physics potential of an $e^+e^-$ Higgs / Top / Electroweak factory, we propose to define a set of focus topics. The general reasoning and the proposed topics are described in this document

Focus topics for the ECFA study on Higgs / Top / EW factories

International audienceIn order to stimulate new engagement and trigger some concrete studies in areas where further work would be beneficial towards fully understanding the physics potential of an $e^+e^-$ Higgs / Top / Electroweak factory, we propose to define a set of focus topics. The general reasoning and the proposed topics are described in this document

Focus topics for the ECFA study on Higgs / Top / EW factories

International audienceIn order to stimulate new engagement and trigger some concrete studies in areas where further work would be beneficial towards fully understanding the physics potential of an $e^+e^-$ Higgs / Top / Electroweak factory, we propose to define a set of focus topics. The general reasoning and the proposed topics are described in this document

Focus topics for the ECFA study on Higgs / Top / EW factories

International audienceIn order to stimulate new engagement and trigger some concrete studies in areas where further work would be beneficial towards fully understanding the physics potential of an $e^+e^-$ Higgs / Top / Electroweak factory, we propose to define a set of focus topics. The general reasoning and the proposed topics are described in this document

Focus topics for the ECFA study on Higgs / Top / EW factories

International audienceIn order to stimulate new engagement and trigger some concrete studies in areas where further work would be beneficial towards fully understanding the physics potential of an $e^+e^-$ Higgs / Top / Electroweak factory, we propose to define a set of focus topics. The general reasoning and the proposed topics are described in this document