Abstract: The invention relates to methods of reducing the immunogenicity of CRISPR-associated (Cas) proteins and the modified Cas proteins produced therefrom. In addition, the invention relates to methods for cell and gene therapy, including any and all genetic modifications and alterations of gene expression (and/or genetic elements) made in-vivo or ex-vivo using Cas proteins with reduced immunogenicity.

Abstract: Antibodies having modified constant regions so as to permit conjugation of the antibody to a payload such as a therapeutic agent are described. Preferred antibodies include a mutation at light chain position 180 (positional numbering), most preferably the mutation is to a residue selected from C, K, Q, or a non-natural amino acid. Additional mutations may also be combined with a mutation at position 180; including one or more of light chain (LC) S208, LC S171, LC S182, LC A184, LC V191, LC S202, LC S203, LC T206, heavy chain (HC) S160, HC T190, HC S443, HC S447, HC S139, HC S168, HC V170, HC V176, HC T200, HC S445 according to a positional numbering convention.

Abstract: Antibodies having modified constant regions so as to permit conjugation of the antibody to a payload such as a therapeutic agent are described. Preferred antibodies include a mutation at light chain position 180 (positional numbering), most preferably the mutation is to a residue selected from C, K, Q, or a non-natural amino acid. Additional mutations may also be combined with a mutation at position 180; including one or more of light chain (LC) S208, LC S171, LC S182, LC A184, LC V191, LC S202, LC S203, LC T206, heavy chain (HC) S160, HC T190, HC S443, HC S447, HC S139, HC S168, HC V170, HC V176, HC T200, HC S445 according to a positional numbering convention.

Abstract: Broadly speaking, the present invention provides a computer-implemented design method and a system to filter a large selection of mutated antibody sequences, identify those mutated antibody sequences which have particular desired properties, such that the identified sequences can be conjugated to a payload and tested in vitro. Thus, the design and system advantageously remove the need for physical testing of the entire initial selection of molecules, which is complex and costly. Only those which match the pre-defined design criteria may be subject to further experimental testing (in vitro testing) to confirm the results of the computer implemented design. Advantageously, by filtering unsafe molecules during the in silico design process, more time can be spent testing drugs which are predicted to be safe for humans.

Abstract: The invention relates to methods of reducing the immunogenicity of CRISPR-associated (Cas) proteins and the modified Cas proteins produced therefrom. In addition, the invention relates to methods for cell and gene therapy, including any and all genetic modifications and alterations of gene expression (and/or genetic elements) made in-vivo or ex-vivo using Cas proteins with reduced immunogenicity.

Abstract: Antibodies having modified constant regions so as to permit conjugation of the antibody to a payload such as a therapeutic agent are described. Preferred antibodies include a mutation at light chain position 180 (positional numbering), most preferably the mutation is to a residue selected from C, K, Q, or a non-natural amino acid. Additional mutations may also be combined with a mutation at position 180; including one or more of light chain (LC) S208, LC S171, LC S182, LC A184, LC V191, LC S202, LC S203, LC T206, heavy chain (HC) S160, HC T190, HC S443, HC S447, HC S139, HC S168, HC V170, HC V176, HC T200, HC S445 according to a positional numbering convention.

Abstract: This invention relates to the modification of the amino acid sequence of an immunoglobulin molecule at certain key positions within regions of the VH and VL FR and CDR3 domains and/or the CH1 domain which are prone to aggregation. Immunoglobulins modified as described may display improved manufacturability, for example, reduced aggregation propensity and/or increased production levels.

Abstract: This invention relates to the modification of the amino acid sequence of an immunoglobulin molecule at certain key positions within regions of the VH and VL FR and CDR3 domains and/or the CH1 domain which are prone to aggregation. Immunoglobulins modified as described may display improved manufacturability, for example, reduced aggregation propensity and/or increased production levels.

Abstract: This invention relates to the modification of the amino acid sequence of an immunoglobulin molecule at certain key positions within regions of the VH and VL FR and CDR3 domains and/or the CH1 domain which are prone to aggregation. Immunoglobulins modified as described may display improved manufacturability, for example, reduced aggregation propensity and/or increased production levels.

Abstract: A prediction method for predicting the effect of an amino acid modification on the rate of aggregation (solubility) of a reference polypeptide comprising: calculating the difference in hydrophobicity (?Hydr) between the reference polypeptide and a modified polypeptide, calculating the difference in ?-sheet propensity (??Gcoil-?+??G?-coil) between the reference polypeptide and modified polypeptide, calculating the difference in charge (? Charge) between the reference polypeptide and modified polypeptide, and calculating: [x* ?Hydr]+[y*(??Gcoil-?+??G?-coil)]?[z*? Charge], wherein x, y and z are scaling factors.

Abstract: The present invention provides methods of predicting protein aggregation and designing aggregation inhibitors. One such method for predicting potential protein aggregation inhibiting peptide sequences, includes the steps of: a) identifying a peptide sequence forming at least part of an aggregation region in a target protein; b) testing whether said peptide sequence forms part of a ?-sheet; c) if a positive result is achieved in step b), extracting the adjacent strands of that sheet; d) identifying residues in the adjacent strands to said peptide sequence whose side chains interact with said peptide sequence, those residues forming a potential protein aggregation inhibiting peptide sequence. The present invention also provides methods of designing compounds using the residues identified in the above method; compounds produced by the methods and computer programs for carrying out the above methods.

Abstract: This invention relates to the modification of the amino acid sequence of an immunoglobulin molecule at certain key positions within regions of the VH and VL FR and CDR3 domains and/or the CH1 domain which are prone to aggregation. Immunoglobulins modified as described may display improved manufacturability, for example, reduced aggregation propensity and/or increased production levels.

Abstract: A method of determining aggregation rate data predicting an aggregation rate of a polypeptide defined by an amino acid sequence, the method comprising determining a hydrophobicity value, a charge value, and at least one shape propensity value for said sequence; identifying one or more aggregation-influencing patterns within said sequence; determining a pattern value for the sequence responsive to said identifying; and determining said aggregation rate data by determining a weighted combination of said hydrophobicity value, said charge value, said at least one shape propensity value, said pattern value and at least one factor extrinsic to said amino acid sequence.

Abstract: A prediction method for predicting the effect of an amino acid modification on the rate of aggregation (solubility) of a reference polypeptide comprising: calculating the difference in hydrophobicity (?Hydr) between the reference polypeptide and a modified polypeptide, calculating the difference in ?-sheet propensity (??Gcoil-?+??G?-coil) between the reference polypeptide and modified polypeptide, calculating the difference in charge (? Charge) between the reference polypeptide and modified polypeptide, and calculating: [x*?Hydr]+[y*(??Gcoil-?+??G?-coil)]?[z*?Charge], wherein x, y and z are scaling factors.

Abstract: A method of determining aggregation rate data predicting an aggregation rate of a polypeptide defined by an amino acid sequence, the method comprising determining a hydrophobicity value, a charge value, and at least one shape propensity value for said sequence; identifying one or more aggregation-influencing patterns within said sequence; determining a pattern value for the sequence responsive to said identifying; and determining said aggregation rate data by determining a weighted combination of said hydrophobicity value, said charge value, said at least one shape propensity value, said pattern value and at least one factor extrinsic to said amino acid sequence.

Abstract: The present invention provides methods of predicting protein aggregation and designing aggregation inhibitors. One such method for predicting potential protein aggregation inhibiting peptide sequences, includes the steps of: a) identifying a peptide sequence forming at least part of an aggregation region in a target protein; b) testing whether said peptide sequence forms part of a ?-sheet; c) if a positive result is achieved in step b), extracting the adjacent strands of that sheet; d) identifying residues in the adjacent strands to said peptide sequence whose side chains interact with said peptide sequence, those residues forming a potential protein aggregation inhibiting peptide sequence. The present invention also provides methods of designing compounds using the residues identified in the above method; compounds produced by the methods and computer programs for carrying out the above methods.

Abstract: A method of determining aggregation rate data predicting an aggregation rate of a polypeptide defined by an amino acid sequence, the method comprising determining a hydrophobicity value, a charge value, and at least one shape propensity value for said sequence; identifying one or more aggregation-influencing patterns within said sequence; determining a pattern value for the sequence responsive to said identifying; and determining said aggregation rate data by determining a weighted combination of said hydrophobicity value, said charge value, said at least one shape propensity value, said pattern value and at least one factor extrinsic to said amino acid sequence.

Abstract: This invention relates to the inhibition of alpha-synuclein aggregation using peptidyl compounds which are retroenantiomers of the alpha-synuclein sequence, in particular retroenantiomers of sequences in the regions between residues 1 to 60 or residues 61 to 96. Peptidyl compounds of the invention may optionally be coupled to doperminergic targeting moieties and/or blood brain barrier transport moieties and may be useful in the treatment of alpha-synucleinopathies such as Parkinson's disease.

Abstract: A prediction method for predicting the effect of an amino acid modification on the rate of aggregation (solubility) of a reference polypeptide comprising: calculating the difference in hydrophobicity (?Hydr) between the reference polypeptide and a modified polypeptide, calculating the difference in ?-sheet propensity (??Gcoil-?+??G?-coil) between the reference polypeptide and modified polypeptide, calculating the difference in charge (? Charge) between the reference polypeptide and modified polypeptide, and calculating: [x*?Hydr]+[y*(??Gcoil-?+??G?-coil)]?[z*? Charge], wherein x, y and z are scaling factors.

Abstract: The present invention relates to the targeting and clearance of soluable unprocessed Islet Amyloid Polypeptide (hIAPP) in order to prevent the nucleation of hIAPP amyloidogenesis and to interfere with pancreatic cell death which is associated with the aggregation of hIAPP. Agents and methods for reducing hIAPP aggregation are provided herein and may be useful in the treatment of type 2 diabetes.