Cambridge University Technical Services Limited

Lonza Biologics Plc

Jesus Zurdo

Christopher Martin Dobson

Fabrizio Chiti

Michele Vendruscolo

Kateri Hayashi DuBay

Yvette Stallwood

Rebecca Michael

Andreas Arnell

Jose Jimenez

Kai J Kohlhoff

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.

Variant immunoglobulins with improved manufacturability

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 (&#x394;Hydr) between the reference polypeptide and a modified polypeptide, calculating the difference in &#x3b2;-sheet propensity (&#x394;&#x394;G+&#x394;&#x394;G) between the reference polypeptide and modified polypeptide, calculating the difference in charge (&#x394; Charge) between the reference polypeptide and modified polypeptide, and calculating: [x* &#x394;Hydr]+[y*(&#x394;&#x394;G+&#x394;&#x394;G)]&#x2212;[z*&#x394; Charge], wherein x, y and z are scaling factors.

Computational method and apparatus for predicting polypeptide aggregation or solubility

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 &#x3b2;-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.

Method for predicting protein aggregation and designing aggregation inhibitors

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.

Method and apparatus for assessing polypeptide aggregation

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 (&#x394;Hydr) between the reference polypeptide and a modified polypeptide, calculating the difference in &#x3b2;-sheet propensity (&#x394;&#x394;G+&#x394;&#x394;G) between the reference polypeptide and modified polypeptide, calculating the difference in charge (&#x394; Charge) between the reference polypeptide and modified polypeptide, and calculating: [x*&#x394;Hydr]+[y*(&#x394;&#x394;G+&#x394;&#x394;G)]&#x2212;[z*&#x394;Charge], wherein x, y and z are scaling factors.

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 (&#x394;Hydr) between the reference polypeptide and a modified polypeptide, calculating the difference in &#x3b2;-sheet propensity (&#x394;&#x394;G+&#x394;&#x394;G) between the reference polypeptide and modified polypeptide, calculating the difference in charge (&#x394; Charge) between the reference polypeptide and modified polypeptide, and calculating: [x*&#x394;Hydr]+[y*(&#x394;&#x394;G+&#x394;&#x394;G)]&#x2212;[z*&#x394; Charge], wherein x, y and z are scaling factors.

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Cambridgeshire, United Kingdom

Jesus Zurdo