Bn Immunotherapeutics, Inc.

Pharmexa A/s

H. Lundbeck A/s

Mipsalus Aps

Bavarian Nordic A/s

Klaus Gregorius Nielsen

Peter Birk Rasmussen

Lucilla Steinaa

Søren Mouritsen

Iben Dalum

Dana Leach

Gunilla Karlsson

Anand Gautam

Martin Roland Jensen

Marie Eskling

Peter Koefoed

Jesper Haaning

Jesper Svenning Kristensen

Nicolas Otto Krogh

Soren Mouritsen

Jesper Hanning

Florence Dal Degan

Nicholas O Krogh

Peter Birk

Disclosed are novel methods and compositions for combating diseases characterized by deposition of amyloid. The methods generally rely on immunization against amyloid precursor protein (APP) or beta amyloid (A&#x3b2;). Immunization is preferably effected by administration of analogs of autologous APP or A&#x3b2;, said analogs being capable of inducing antibody production against the autologous amyloidogenic polypeptides. Especially preferred as an immunogen is autologous A&#x3b2; which has been modified by introduction of one single or a few foreign, immunodominant and promiscuous T-cell epitopes. Such methods and means include methods for the preparation of analogs and pharmaceutical formulations, as well as nucleic acid fragments, vectors, transformed cells, polypeptides and pharmaceutical formulations.

Amyloid-beta polypeptide vaccine

One aspect is a method for improved preparation of molecular imprinted polymer (MIP) particles, where initial compositions comprising insoluble MIP particles are enriched for those MIP particles that bind a particular target molecule, thus excluding non-binding and weakly binding particles from the final composition. Enrichment is typically accomplished via use of chromatographic methods capable of separating particulate material or by means of agglutination. Another aspect is preparation of improved insoluble MIPs by use of extended micronization of raw MIP particles with a view to expose a large number of binding sites per mass unit of MIP particles. In preferred embodiments the two aspects are combined. The resulting improved MIPs may be used for diagnostic, analytical and therapeutic purposes, notably as orally administered drugs which can bind substances such as cholesterol and bile acids and bile acid salts in the gastrointestinal tract.

Preparation of molecular imprinted polymers

The present invention provides for a novel method for purification of EGFR family proteins obtained from cultures of insect cells. The process comprises subsequent steps of a) diafiltration and exchange of culture medium with buffer, b) immobilized metal affinity chromatography (IMAC), C) size exclusion chromatography (SEC), and d) anion exchange chromatography (AIE). The method also provides for an immunogenic variant of HER-2 protein which for which the purification process has been especially adapted, as well as means for the preparation of the variant.

Immunogenic HER-2 variants

A method is disclosed for inducing cell-mediated immunity against cellular antigens. More specifically, the invention provides for a method for inducing cytotoxic T-lymphocyte immunity against weak antigens, notably self-proteins. The method entails that antigen presenting cells are induced to present at least one CTL epitope of the weak antigen and at the same time presenting at least one foreign T-helper lymphocyte epitope. In a preferred embodiment, the antigen is a cancer specific antigen, e.g. PSM, Her2, or FGF8b. The method can be exercised by using traditional polypeptide vaccination, but also by using live attenuated vaccines or nucleic acid vaccination. The invention furthermore provides immunogenic analogues of PSM, Her2 and FGF8b, as well as nucleic acid molecules encoding these analogues. Also vectors and transformed cells are disclosed. The invention also provides for a method for identification of immunogenic analogues of weak or non-immunogenic antigens.

Methods for therapeutic vaccination

A method is disclosed for inducing cell-mediated immunity against cellular antigens. More specifically, the invention provides for a method for inducing cytotoxic T-lymphocyte immunity against weak antigens, notably self-proteins. The method entails that antigen presenting cells are induced to present at least one CTL epitope of the weak antigen and at the same time presenting at least one foreign T-helper lymphocyte epitope. In a preferred embodiment, the antigen is a cancer specific antigen, e.g. PSM, Her2, or FGF8. The method can be exercised by using traditional polypeptide vaccination, but also by using live attenuated vaccines or nucleic acid vaccination. The invention furthermore provides immunogenic analogues of PSM, Her2 and FGF8, as well as nucleic acid molecules encoding these analogues. Also vectors and transformed cells are disclosed. The invention also provides for a method for identification of immunogenic analogues of weak or non-immunogenic antigens.

The present invention provides for a novel method for purification of EGFR family proteins obtained from cultures of insect cells. The process comprises subsequent steps of a) diafiltration and exchange of culture medium with buffer, b) immobilized metal affinity chromatography (IMAC), c) size exclusion chromatography (SEC), and d) anion exchange chromatography (AIE). The method also provides for an immunogenic variant of HER-2 protein for which the purification process has been especially adapted, as well as means for the preparation of the variant.

Purification of HER-2 variants

A method for in vivo down-regulation of amyloid protein in an animal, including a human being, the method comprising effecting presentation to the animal's immune system of an immunogenically effective amount of at least one amyloidogenic polypeptide or subsequence thereof which has been formulated so that immunization of the animal with the amyloidgenic polypeptide or subsequence thereof induces production of antibodies against the amyloidogenic polypeptide, and/or at least one analogue of the amyloidogenic polypeptide wherein is introduced at least one modification in the amino acid sequence of the amyloidogenic polypeptide which has as a result the immunization of the animal with the analogue induces production of antibodies against the amyloidogenic polypeptide.

Method for down-regulation of amyloid

The present invention provides for novel immungens that are comprised of an activated polyhydroxypolymer backbone to which is attached 2 separate antigenic determinants. The 1st antigenic determinant includes a B-cell or CTL epitope and the 2nd antigenic determinant includes a T-helper epitope. In preferred embodiments, the antigenic determinants are derived from different molecules and species. Exemplary immunogens of the invention are constituted of a linear tresyl-activated dextran backbone to which is coupled B-cell or CTL epitopes of an antigen and to which is also coupled universal T-helper epitopes. Also disclosed are immunogenic compositions comprising the immunogens, methods of immunization and a method for identification of suitable immunogens of the invention.

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Søborg, Denmark

Klaus Gregorius Nielsen