Relationship between potential aggregation-prone regions and HLA-DR-binding T-cell immune epitopes: Implications for rational design of novel and follow-on therapeutic antibodies

Journal of Pharmaceutical Sciences

Volumn 101, Issue 8, 2012, Pages 2686-2701

  Kumar, Sandeep ^a   Mitchell, Mark A ^a   Rup, Bonita ^a   Singh, Satish K ^a  

^a PFIZER INC   (United States)

Author keywords

Bioinformatics; Biopharamaceutics; Computer aided drug design; Drug; Immune epitopes; MAbs; Protein aggregation; Proteins

Indexed keywords

ADALIMUMAB; ALEMTUZUMAB; AMYLOID; ARCITUMOMAB TC 99M; AUTOANTIGEN; BASILIXIMAB; BEVACIZUMAB; CANAKINUMAB; CERTOLIZUMAB PEGOL; DACLIZUMAB; DENOSUMAB; ECULIZUMAB; EPITOPE; GEMTUZUMAB; GEMTUZUMAB OZOGAMICIN; HLA DR ANTIGEN; HLA DRB1 ANTIGEN; IMMUNOGLOBULIN G; IMMUNOGLOBULIN HEAVY CHAIN; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; MONOCLONAL ANTIBODY; OFATUMUMAB; OMALIZUMAB; PANITUMUMAB; RANIBIZUMAB; RITUXIMAB; TOCILIZUMAB; TRASTUZUMAB; UNINDEXED DRUG; USTEKINUMAB;

ALLELE; AMINO ACID SEQUENCE; ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG MANUFACTURE; DRUG SAFETY; GENE LOCUS; HUMAN; HYDROPHOBICITY; IMMUNE RESPONSE; IMMUNOGENICITY; PROTEIN MOTIF; REGULATORY T LYMPHOCYTE; SEQUENCE ANALYSIS; T LYMPHOCYTE;

EID: 84862893136     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.23169     Document Type: Article

References (71)

1. Baker MP, Reynolds HM, Lumicisi B, Bryson CJ. 2010. Immunogenicity of protein therapeutics: The key causes, consequences and challenges. Self Nonself 1(4):314-322.
2. Harding FA, Stickler MM, Razo J, DuBridge RB. 2010. The immunogenicity of humanized and fully human antibodies: Residual immunogenicity resides in the CDR regions. MAbs 2(3):256-265.
3. Nelson AL, Dhimolea E, Reichert JM. 2010. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9(10):767-774.
4. Koren E, De Groot AS, Jawa V, Beck KD, Boone T, Rivera D, Li L, Mytych D, Koscec M, Weeraratne D, Swanson S, Martin W. 2007. Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein. Clin Immunol 124(1):26-32.
5. Schellekens H. 2002. Immunogenicity of therapeutic proteins: Clinical implications and future prospects. Clin Ther 24(11):1720-1740.
6. Buttel IC, Chamberlain P, Chowers Y, Ehmann F, Greinacher A, Jefferis R, Kramer D, Kropshofer H, Lloyd P, Lubiniecki A, Krause R, Mire-Sluis A, Platts-Mills T, Ragheb JA, Reipert BM, Schellekens H, Seitz R, Stas P, Subramanyam M, Thorpe R, Trouvin JH, Weise M, Windisch J, Schneider CK. 2011. Taking immunogenicity assessment of therapeutic proteins to the next level. Biologicals 39(2):100-109.
7. Malucchi S, Bertolotto, A. 2008. Clinical aspects of immunogenicity to biopharmaceuticals. In Immunogenicity of biopharmaceuticals; Weert M, Møller EH, Eds.Vol. VIII. Springer, New York, pp 27-56.
8. Conrad DH, Gibb DR, Sturgill J. 2010. Regulation of the IgE response. F1000 Biol Rep 2.
9. Rosenberg AS. 2006. Effects of protein aggregates: An immunologic perspective. AAPS J 8(3):E501-E507.
10. Sauerborn M, Brinks V, Jiskoot W, Schellekens H. 2010. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci 31(2):53-59.
11. Kumar S, Singh SK, Wang X, Rup B, Gill D. 2011. Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions. Pharm Res 28(5):949-961.
12. Stas P, Lasters I. 2009. Strategies for preclinical immunogenicity assessment of protein therapeutics. IDrugs 12(3):169-173.
13. Ghaderi D, Taylor RE, Padler-Karavani V, Diaz S, Varki A. 2010. Implications of the presence of N-glycolylneuraminic acid in recombinant therapeutic glycoproteins. Nat Biotechnol 28(8):863-867.
14. Richard J, Prang N. 2010. The formulation and immunogenicity of therapeutic proteins: Product quality as a key factor. IDrugs 13(8):550-558.
15. Brennan FR, Morton LD, Spindeldreher S, Kiessling A, Allenspach R, Hey A, Muller PY, Frings W, Sims J. 2010. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. MAbs 2(3):233-255.
16. Singh SK. 2011. Impact of product-related factors on immunogenicity of biotherapeutics. J Pharm Sci 100(2):354-387.
17. Pisal DS, Kosloski MP, Middaugh CR, Bankert RB, Balu-Iyer SV. 2012. Native-like aggregates of factor VIII are immunogenic in von Willebrand factor deficient and hemophilia a mice. J Pharm Sci.
18. Fradkin AH, Carpenter JF, Randolph TW. 2009. Immunogenicity of aggregates of recombinant human growth hormone in mouse models. J Pharm Sci 98(9):3247-3264.
19. van Beers MM, Jiskoot W, Schellekens H. 2010. On the role of aggregates in the immunogenicity of recombinant human interferon beta in patients with multiple sclerosis. J Interferon Cytokine Res 30(10):767-775.
20. van Beers MM, Sauerborn M, Gilli F, Brinks V, Schellekens H, Jiskoot W. 2010. Aggregated recombinant human interferon beta induces antibodies but no memory in immune-tolerant transgenic mice. Pharm Res 27(9):1812-1824.
21. van Beers MM, Sauerborn M, Gilli F, Hermeling S, Brinks V, Schellekens H, Jiskoot W. 2010. Hybrid transgenic immune tolerant mouse model for assessing the breaking of B cell tolerance by human interferon beta. J Immunol Methods 352(1-2):32-37.
22. van Beers MM, Sauerborn M, Gilli F, Brinks V, Schellekens H, Jiskoot W. 2011. Oxidized and aggregated recombinant human interferon beta is immunogenic in human interferon beta transgenic mice. Pharm Res 28(10):2393-2402.
23. Barbosa MDFS VJ, Chu S, Smith DD, Jacinto J. 2006. Clinical link between MHC class II haplotype and interferon-beta (IFN-beta) immunogenicity. Clin Immunol 118(1):42-50.
24. De Groot AS, Moise L. 2007. Prediction of immunogenicity for therapeutic proteins: State of the art. Curr Opin Drug Discov Devel 10(3):332-340.
25. De Groot AS, McMurry J, Moise L. 2008. Prediction of immunogenicity: In silico paradigms, ex vivo and in vivo correlates. Curr Opin Pharmacol 8(5):620-626.
26. Hermeling S, Schellekens H, Maas C, Gebbink MF, Crommelin DJ, Jiskoot W. 2006. Antibody response to aggregated human interferon alpha2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J Pharm Sci 95(5):1084-1096.
27. Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C, Grothe R, Eisenberg D. 2005. Structure of the cross-beta spine of amyloid-like fibrils. Nature 435(7043):773-778.
28. Sawaya MR, Sambashivan S, Nelson R, Ivanova MI, Sievers SA, Apostol MI, Thompson MJ, Balbirnie M, Wiltzius JJ, McFarlane HT, Madsen AO, Riekel C, Eisenberg D. 2007. Atomic structures of amyloid cross-beta spines reveal varied steric zippers. Nature 447(7143):453-457.
29. Ivanova MI, Sievers SA, Sawaya MR, Wall JS, Eisenberg D. 2009. Molecular basis for insulin fibril assembly. Proc Natl Acad Sci U S A 106(45):18990-18995.
30. Ivanova MI, Thompson MJ, Eisenberg D. 2006. A systematic screen of beta(2)-microglobulin and insulin for amyloid-like segments. Proc Natl Acad Sci U S A 103(11):4079-4082.
31. Maas C, Hermeling S, Bouma B, Jiskoot W, Gebbink MF. 2007. A role for protein misfolding in immunogenicity of biopharmaceuticals. J Biol Chem 282(4):2229-2236.
32. Kumar S, Wang X, Singh SK. 2010. Identification and impact of aggregation-prone regions in proteins and therapeutic monoclonal antibodies. In Aggregation of therapeutic proteins; Wang W, Roberts CJ, Eds. John Wiley & Sons, Inc., Hoboken, New Jersey, pp 103-118.
33. Agrawal NJ, Kumar S, Wang X, Helk B, Singh SK, Trout BL. 2011. Aggregation in protein-based biotherapeutics: Computational studies and tools to identify aggregation-prone regions. J Pharm Sci 100(12):5081-5095.
34. Bryson CJ, Jones TD, Baker MP. 2010. Prediction of immunogenicity of therapeutic proteins: Validity of computational tools. BioDrugs 24(1):1-8.
35. Tartaglia GG, Cavalli A, Pellarin R, Caflisch A. 2005. Prediction of aggregation rate and aggregation-prone segments in polypeptide sequences. Protein Sci 14(10):2723-2734.
36. Fernandez-Escamilla AM, Rousseau F, Schymkowitz J, Serrano L. 2004. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat Biotechnol 22(10):1302-1306.
37. Wang X, Singh SK, Kumar S. 2010. Potential aggregation-prone regions in complementarity-determining regions of antibodies and their contribution towards antigen recognition: A computational analysis. Pharm Res 27(8):1512-1529.
38. Wang P, Sidney J, Dow C, Mothe B, Sette A, Peters B. 2008. A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach. PLoS Comput Biol 4(4):e1000048.
39. Rotzschke O, Falk K. 1994. Origin, structure and motifs of naturally processed MHC class II ligands. Curr Opin Immunol 6(1):45-51.
40. Rammensee HG. 1995. Chemistry of peptides associated with MHC class I and class II molecules. Curr Opin Immunol 7(1):85-96.
41. + T-cell epitopes on the tumor antigen MAGE-3. Blood 101(3):1038-1044.
42. Zhang GL, Khan AM, Srinivasan KN, August JT, Brusic V. 2005. MULTIPRED: A computational system for prediction of promiscuous HLA binding peptides. Nucleic Acids Res 33(Web Server issue):W172-179.
43. Thompson JD, Higgins DG, Gibson TJ. 1994. CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22(22):4673-4680.
44. Wang X, Das TK, Singh SK, Kumar S. 2009. Potential aggregation prone regions in biotherapeutics: A survey of commercial monoclonal antibodies. MAbs 1(3):254-267.
45. Thompson MJ, Sievers SA, Karanicolas J, Ivanova MI, Baker D, Eisenberg D. 2006. The 3D profile method for identifying fibril-forming segments of proteins. Proc Natl Acad Sci U S A 103(11):4074-4078.
46. Lopez de la Paz M, Serrano L. 2004. Sequence determinants of amyloid fibril formation. Proc Natl Acad Sci U S A 101(1):87-92.
47. Vita R, Zarebski L, Greenbaum JA, Emami H, Hoof I, Salimi N, Damle R, Sette A, Peters B. 2010. The immune epitope database 2.0. Nucleic Acids Res 38(Database issue):D854-D862.
48. Southwood S, Sidney J, Kondo A, del Guercio MF, Appella E, Hoffman S, Kubo RT, Chesnut RW, Grey HM, Sette A. 1998. Several common HLA-DR types share largely overlapping peptide binding repertoires. J Immunol 160(7):3363-3373.
49. Wang P, Sidney J, Kim Y, Sette A, Lund O, Nielsen M, Peters B. 2010. Peptide binding predictions for HLA DR, DP and DQ molecules. BMC Bioinformatics 11:568.
50. De Groot AS, Martin W, Rivera DS. 2011. Regulatory T cell epitopes, compositions and uses thereof. Patent US7884184B2.
51. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. 2000. The Protein Data Bank. Nucleic Acids Res 28(1):235-242.
52. Godkin AJ, Smith KJ, Willis A, Tejada-Simon MV, Zhang J, Elliott T, Hill AV. 2001. Naturally processed HLA class II peptides reveal highly conserved immunogenic flanking region sequence preferences that reflect antigen processing rather than peptide-MHC interactions. J Immunol 166(11):6720-6727.
53. Jorgensen KW, Buus S, Nielsen M. 2010. Structural properties of MHC class II ligands, implications for the prediction of MHC class II epitopes. PLoS One 5(12):e15877.
54. De Groot AS, Moise L, McMurry JA, Wambre E, Van Overtvelt L, Moingeon P, Scott DW, Martin W. 2008. Activation of natural regulatory T cells by IgG Fc-derived peptide "Tregitopes". Blood 112(8):3303-3311.
55. Chennamsetty N, Voynov V, Kayser V, Helk B, Trout BL. 2009. Design of therapeutic proteins with enhanced stability. Proc Natl Acad Sci U S A 106(29):11937-11942.
56. Kumar S, Bansal M. 1998. Dissecting alpha-helices: Position-specific analysis of alpha-helices in globular proteins. Proteins 31(4):460-476.
57. Mant CT, Kovacs JM, Kim HM, Pollock DD, Hodges RS. 2009. Intrinsic amino acid side-chain hydrophilicity/hydrophobicity coefficients determined by reversed-phase high-performance liquid chromatography of model peptides: Comparison with other hydrophilicity/hydrophobicity scales. Biopolymers 92(6):573-595.
58. Lee KH, Wucherpfennig KW, Wiley DC. 2001. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat Immunol 2(6):501-507.
59. Ciszak E, Smith GD. 1994. Crystallographic evidence for dual coordination around zinc in the T3R3 human insulin hexamer. Biochemistry 33(6):1512-1517.
60. Rathore A. 2010. Implementation of Quality by Design (QbD) for biopharmaceutical products. PDA J Pharm Sci Technol 64(6):495-496.
61. Brummitt RK, Nesta DP, Chang L, Chase SF, Laue TM, Roberts CJ. 2011. Nonnative aggregation of an IgG1 antibody in acidic conditions: Part 1. Unfolding, colloidal interactions, and formation of high-molecular-weight aggregates. J Pharm Sci 100(6):2087-2103.
62. Ramshini H, Parrini C, Relini A, Zampagni M, Mannini B, Pesce A, Saboury AA, Nemat-Gorgani M, Chiti F. 2011. Large proteins have a great tendency to aggregate but a low propensity to form amyloid fibrils. PLoS One 6(1):e16075.
63. Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool S, Gurlo T, Butler P, Glabe CG. 2007. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener 2:18.
64. Yanamandra K, Gruden MA, Casaite V, Meskys R, Forsgren L, Morozova-Roche LA. 2011. Alpha-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients. PLoS One 6(4):e18513.
65. Buck PM, Kumar S, Wang X, Agrawal NJ, Trout BL, Singh SK. 2011. Computational methods to predict therapeutic protein aggregation. In Therapeutic proteins: Methods and protocols; Voynov V and Caravella JA, Eds. 2nd ed. (Methods in molecular biology)New York: Humana Press, in press.
66. Lange C, Durr M, Doster H, Melms A, Bischof F. 2007. Dendritic cell-regulatory T-cell interactions control self-directed immunity. Immunol Cell Biol 85(8):575-581.
67. Perchiacca JM, Bhattacharya M, Tessier PM. 2011. Mutational analysis of domain antibodies reveals aggregation hotspots within and near the complementarity determining regions. Proteins 79(9):2637-2647.
68. Pepinsky RB, Silvian L, Berkowitz SA, Farrington G, Lugovskoy A, Walus L, Eldredge J, Capili A, Mi S, Graff C, Garber E. 2010. Improving the solubility of anti-LINGO-1 monoclonal antibody Li33 by isotype switching and targeted mutagenesis. Protein Sci 19(5):954-966.
69. Conley GP, Viswanathan M, Hou Y, Rank DL, Lindberg AP, Cramer SM, Ladner RC, Nixon AE, Chen J. 2011. Evaluation of protein engineering and process optimization approaches to enhance antibody drug manufacturability. Biotechnol Bioeng 108(11):2634-2644.
70. Wu SJ, Luo J, O'Neil KT, Kang J, Lacy ER, Canziani G, Baker A, Huang M, Tang QM, Raju TS, Jacobs SA, Teplyakov A, Gilliland GL, Feng Y. 2010. Structure-based engineering of a monoclonal antibody for improved solubility. Protein Eng Des Sel 23(8):643-651.
71. Dudgeon K, Famm K, Christ D. 2009. Sequence determinants of protein aggregation in human VH domains. Protein Eng Des Sel 22(3):217-220.