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Geneva, Switzerland

Disclosed are processes for producing a variant polypeptide (e.g. antibodies) having modified binding characteristics for human Fc gamma receptor IIA (CD32A) leading to increased inhibition of proinflammatory mediators while retaining binding to a target antigen via its Fv portion, which processes comprise altering the polypeptides by substitution of at least two amino acid residues at EU position 325, 326 or 328 of a human IgG CH2 region for a sequence selected from SAAF, SKAF, NAAF and NKAF. Also disclosed are molecules, particularly polypeptides, more particularly immunoglobulins (e.g. antibodies) that include a variant CDR3 region, wherein the variant CDR3 region includes at least one amino acid modified relative to a wild-type CDR3 region. The polypeptides that can be generated according to the methods of the invention are highly variable, and they can include antibodies and fusion proteins that contain an Fc region or a biologically active portion thereof.

The invention provides compositions and methods for generating libraries of DNA sequences encoding homologous polypeptides, and uses of the libraries to identify naturally diversified polypeptide variants. The invention also provides compositions and methods for generating collections of synthetic antibody fragments in which one or several complementary determining regions (CDR) are replaced by a collection of the corresponding CDR captured from a natural source. The invention further provides compositions and methods for diversifying a portion of a polypeptide by inserting a diversified sequence of synthetic or natural origin without the need for modification of the original polypeptide coding sequence.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.4.4-1 | Award Amount: 11.24M | Year: 2012

Hemophagocytic lymphohistiocytosis (HLH) is a rare, devastating disease characterized by uncontrolled immune response that primarily affects young infants and children. HLH is usually fatal if untreated. Even when treated, the overall survival rate is still as low as 60-70%. No drug has been formally developed for the treatment of this disease and current treatment methods require the use of drugs which have not formally been developed for this indication which have an unfavourable safety profile. The cytokine interferon-gamma (IFN) was shown to play a key pathological role in the disease. It has been demonstrated that neutralization of IFN with a monoclonal antibody (mAb) reverts the disease and rescues animals from death in murine models of primary HLH. In patients, evidence points towards a correlation between levels of IFN and disease activity. In order to target IFN in patients with HLH, NovImmune generated and characterized a fully human mAb, NI-0501, that neutralizes the biological activity of human IFN. This consortium proposes an adaptive clinical trial with a pilot and a pivotal phase to provide the necessary data for Market Access Authorization for NI-0501 in HLH. The pilot phase will enroll only patients well-known to have a primary form of HLH and who relapsed after having responded to an initial treatment while the pivotal phase will open the recruitment to newly diagnosed HLH patients. The transition between the pilot and the pivotal phase will be governed by strict pre-defined transition rules and will only occur if a favorable benefit-risk profile has been demonstrated. During the course of the pilot phase the consortium will attempt to generate the necessary information to justify the inclusion in the pivotal phase of a broad range of HLH patient (secondary forms of the disease), for which the pivotal role of IFN will have been demonstrated thanks to the research activities of members of the consortium.

NovImmune | Date: 2014-10-06

This invention provides fully human monoclonal antibodies that recognize IL-17F and/or the heterodimeric IL-17A/IL-17F complex, but do not recognize IL-17A. The invention further provides methods of using such monoclonal antibodies as a therapeutic, diagnostic, and prophylactic.

This invention relates generally to methods and compositions for diagnosing and treating disorders associated with elevated levels of Toll-like Receptor 4 (TLR4) ligands and other biomarkers. The invention also relates to methods of treating, delaying the progression of, or otherwise ameliorating a symptom of a disorder associated with elevated levels of TLR4 ligands and other biomarkers using agents that interfere with or otherwise antagonize TLR4 signaling, including neutralizing anti-TLR4 antibodies.

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