Human islet amyloid polypeptide (hiapp) specific antibodies and uses thereof

Abstract

Provided are novel human islet amyloid polypeptide, also known as amylin and IAPP and proIAPP respectively, specific antibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for IAPP and/or proIAPP are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for IAPP and/or proIAPP targeted immunotherapy and diagnostics, respectively.

1 . A human monoclonal anti-islet amyloid polypeptide (IAPP) antibody. 
     
     
         2 . The antibody of  claim 1 , which is capable of binding human IAPP and/or proIAPP. 
     
     
         3 . The antibody of  claim 1  or  2 , which does not substantially recognize amyloid-β peptide (Aβ 1-42 ). 
     
     
         4 . The antibody of any one  claims 1  to  3 , which does not substantially recognize physiological IAPP. 
     
     
         5 . The antibody of any one of  claims 1  to  4 , which does not substantially recognize proIAPP. 
     
     
         6 . The antibody of any one  claims 1  to  5 , wherein the antibody specifically binds an IAPP epitope which comprises the amino acid sequence SSNNFGA (SEQ ID NO: 4), CNTATCA (SEQ ID NO: 5), or QRLANFLVHS (SEQ ID NO: 71). 
     
     
         7 . The antibody of any one of  claims 1  to  6  or an IAPP and/or proIAPP binding fragment thereof comprising in its variable region at least one complementarity determining region (CDR) as depicted in  FIG. 1  and/or one or more CDRs thereof comprising one or more amino acid substitutions. 
     
     
         8 . The antibody or binding fragment of  claim 7  comprising an amino acid sequence of the V H  and/or V L  region as depicted in  FIG. 1  or a V H  and/or V L  region thereof comprising one or more amino acid substitutions. 
     
     
         9 . The antibody of any one of  claims 1  to  8 , which preferentially recognizes IAPP aggregates comprising IAPP oligomers and/or fibrils over physiological IAPP. 
     
     
         10 . The antibody of any one  claims 1  to  4 , which is capable of binding proIAPP. 
     
     
         11 . The antibody of  claim 10  or a proIAPP binding fragment thereof comprising in its variable region at least one CDR as depicted in  FIG. 2  and/or one or more CDRs thereof comprising one or more amino acid substitutions. 
     
     
         12 . The antibody or binding fragment of  claim 11  comprising an amino acid sequence of the V H  and/or V L  region as depicted in  FIG. 2  or a V H  and/or V L  region thereof comprising one or more amino acid substitutions. 
     
     
         13 . The antibody of any one of  claims 1  to  12  which is a chimeric rodent-human or a rodentized antibody. 
     
     
         14 . An antibody or antigen-binding molecule which competes with an antibody of any one of  claims 1  to  13  for specific binding to IAPP and/or proIAPP. 
     
     
         15 . The antibody of any one of  claims 1  to  14 , which is selected from the group consisting of a single chain Fv fragment (scFv), an F(ab′) fragment, an F(ab) fragment, and an F(ab′) 2  fragment. 
     
     
         16 . A polynucleotide encoding at least the binding domain or variable region of an immunoglobulin chain of the antibody of any one of  claims 1  to  15 . 
     
     
         17 . A vector comprising the polynucleotide of  claim 16 , optionally in combination with a polynucleotide of  claim 16  that encodes the variable region of the other immunoglobulin chain of said binding molecule. 
     
     
         18 . A host cell comprising a polynucleotide of  claim 16  or a vector of  claim 17 . 
     
     
         19 . A method for preparing an anti-IAPP or an anti-proIAPP antibody or immunoglobulin chain(s) thereof, said method comprising
 (a) culturing the cell of  claim 18 ; and   (b) isolating said antibody or immunoglobulin chain(s) thereof from the culture.   
     
     
         20 . An antibody or immunoglobulin chain(s) thereof encoded by a polynucleotide of  claim 16  or obtainable by the method of  claim 19 . 
     
     
         21 . The antibody of any one of  claims 1  to  15  or  20 , which is detectably labeled. 
     
     
         22 . The antibody of  claim 21 , wherein the detectable label is selected from the group consisting of an enzyme, a radioisotope, a fluorophore and a heavy metal. 
     
     
         23 . The antibody of any one of  claims 1  to  15  or  20  to  22 , which is attached to a drug. 
     
     
         24 . A composition comprising the antibody of any one of  claims 1  to  15  or  20  to  23 , the polynucleotide of  claim 16 , the vector of  claim 17  or the cell of  claim 18 . 
     
     
         25 . The composition of  claim 24 , which is a pharmaceutical composition and further comprises a pharmaceutically acceptable carrier. 
     
     
         26 . The composition of  claim 25 , which is a vaccine. 
     
     
         27 . The composition of  claim 25  or  26  further comprising an additional agent useful for treating diabetes mellitus type 2 (T2D) and/or in treating or preventing islet rejection following clinical pancreatic islet transplantation. 
     
     
         28 . The composition of  claim 24 , which is a diagnostic composition, and optionally comprises reagents conventionally used in immune- or nucleic acid based diagnostic methods. 
     
     
         29 . An antibody of any one of  claims 1  to  15  or  20  to  23  or an IAPP and/or proIAPP binding molecule having substantially the same binding specificities of any one thereof, the polynucleotide of  claim 16 , the vector of  claim 17  or the cell of  claim 18  or a pharmaceutical or diagnostic composition comprising any one thereof for use in prophylactic treatment, therapeutic treatment and/or monitoring the progression or a response to treatment of a disorder related to IAPP and/or proIAPP. 
     
     
         30 . A method of diagnosing or monitoring the progression of islet amyloidosis in a subject is provided, the method comprising determining the presence of IAPP and/or proIAPP oligomers, aggregates or fibrils in a sample from the subject to be diagnosed with at least one antibody of any one of  claims 1  to  15  or  20  to  23  or an IAPP and/or proIAPP binding molecule having substantially the same binding specificities of any one thereof, wherein the presence of IAPP and/or proIAPP oligomers, aggregates or fibrils is indicative of presymptomatic, prodromal or clinical diabetes mellitus type 2 (T2D) and/or of beta-cell failure following clinical pancreatic islet transplantation and an increase of the level of IAPP and/or proIAPP oligomers, aggregates or fibrils in comparison to the level of the physiological IAPP or in comparison to a reference sample derived from a healthy control subject or a control sample from the same subject is indicative for progression of presymptomatic, prodromal or established diabetes mellitus type 2 (T2D) and/or of islet failure following clinical pancreatic islet transplantation in said subject. 
     
     
         31 . An IAPP and/or proIAPP binding molecule comprising at least one CDR of an antibody of any one of  claims 1  to  15  or  20  to  23  for the preparation of a composition for in vivo detection of or targeting a therapeutic and/or diagnostic agent to IAPP and/or proIAPP in the human or animal body. 
     
     
         32 . The IAPP and/or proIAPP binding molecule of  claim 31 , wherein said in vivo detection comprises positron emission tomography (PET), single photon emission tomography (SPECT), near infrared (NIR) optical imaging or magnetic resonance imaging (MRI). 
     
     
         33 . The IAPP and/or proIAPP binding molecule of  claim 31  or  32  for use in the method of  claim 30 . 
     
     
         34 . A peptide having an epitope of proIAPP specifically recognized by an antibody of any one of the  claims 1  to  15  or  20  to  23 . 
     
     
         35 . The peptide of  claim 34 , wherein the peptide comprises an amino acid sequence as defined in  claim 6  or a modified sequence thereof in which one or more amino acids are substituted, deleted and/or added, wherein the peptide is recognized by the antibody of any one of  claims 6  to  15 . 
     
     
         36 . A method for diagnosing islet amyloidosis indicative of presymptomatic or clinical diabetes mellitus type 2 and/or of beta-cell failure following clinical pancreatic islet transplantation in a subject, comprising a step of determining the presence of an antibody that binds to a peptide of  claim 34  or  35  in a biological sample of said subject. 
     
     
         37 . A kit useful in the diagnosis or monitoring the progression of islet amyloidosis, said kit comprising at least one antibody of any one of  claims 1  to  15  or  20  to  23  or an IAPP and/or proIAPP binding molecule having substantially the same binding specificities of any one thereof, the polynucleotide of  claim 16 , the vector of  claim 17  or the cell of  claim 18  and/or the peptide of  claim 34  or  35 , optionally with reagents and/or instructions for use.