Computer-implemented methods of determining protein viscosity

Patent metadata

Field	Value
Publication number	US-10762980-B2
Application number	US-201414891906-A
Country	US
Kind code	B2
Filing date	May 16, 2014
Priority date	May 17, 2013
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

Provided herein are high-throughput methods for identifying a candidate antibody based on viscosity of the candiate antibody.

First claim

What is claimed is:

1. A method for producing a low-viscosity antibody solution, the method comprising:
(a) identifying surface-exposed amino acid residues in tertiary structures of a plurality of antibodies by computing total solvent accessible area (SAA) values for amino acid residues of the antibodies based on partial charge values assigned to side-chain atoms of the antibodies, wherein an amino acid residue is identified as a surface-exposed amino acid residue if it has a SAA of greater than a threshold value;
(b) identifying atoms that are within a distance R and belong to a side-chain of an exposed amino acid residues identified in (a);
(c) computing an atomic spatial charge map (SCM) value for each atom identified in (b), wherein the atomic SCM value is the sum of partial charges of the atoms identified in (b);
(d) computing a SCM score for each of the antibodies based on the atomic SCM values computed in (c); and
(e) predicting relative viscosity of each of the antibodies based on the SCM score computed in (d) by comparing the SCM scores computed in (d) to each other, wherein an antibody is predicted to have a low viscosity if the SCM score computed in (d) is lower than the SCM scores of the other antibodies of the plurality; and
(f) producing a solution comprising the antibody predicted to have a low viscosity.

2. The method of claim 1 , wherein the tertiary structure of the antibodies is a Fab domain or a Fv domain of the antibody.

3. The method of claim 1 , wherein the partial charge in step (a) is assigned using a software tool selected from CHARMM force field, PropKa, Accelrys, and Schrodinger.

4. The method of claim 1 , wherein the threshold value is 1-50 Å 2 .

5. The method of claim 1 , wherein the distance R is 5-20 Å.

6. The method of claim 4 , wherein the threshold value is 10 Å 2 .

7. The method of claim 5 , wherein the distance R is 10 Å.

8. The method of claim 1 , wherein the atomic SCM value in (c) is computed based on a pH value of greater than or equal to 7.

9. The method of claim 1 , wherein the atomic SCM value in (c) is computed based on a pH value of less than or equal to 5.5.

10. The method of claim 1 , wherein the antibody is a monoclonal antibody.

11. The method of claim 1 , wherein the antibody is an antibody fragment.

12. The method of claim 11 , wherein the antibody fragment is a Fv, Fab, Fab′ or F(ab′)2 fragment.

Assignees

• Massachusetts Inst Technology
• Novartis Pharma Ag

Inventors

• Trout Bernhardt Levy
• Helk Bernhard
• Agrawal Neeraj Jagdish

Classifications

• G16B15/00 Primary

  ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations or structure alignment · CPC title

• G01N33/6803

  General methods of protein analysis not limited to specific proteins or families of proteins · CPC title

• G01N33/6854

  Immunoglobulins · CPC title

• G01N11/00

  Investigating flow properties of materials, e.g. viscosity, plasticity; Analysing materials by determining flow properties · CPC title

• G01N2011/006

  Determining flow properties indirectly by measuring other parameters of the system · CPC title