PMID- 22619033
OWN - NLM
STAT- MEDLINE
DCOM- 20121022
LR  - 20120628
IS  - 1520-6017 (Electronic)
IS  - 0022-3549 (Linking)
VI  - 101
IP  - 8
DP  - 2012 Aug
TI  - 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.
PG  - 2686-701
LID - 10.1002/jps.23169 [doi]
AB  - Aggregation and unwanted immunogenicity are hurdles to avoid in successful 
      commercial development of antibody-based therapeutics. In this article, the 
      relationship between aggregation-prone regions (APRs), capable of forming cross-beta 
      motifs/amyloid fibrils, and major histocompatibility complex class II-restricted 
      human leukocyte antigen (HLA)-DR-binding T-cell immune epitopes (TcIEs) is 
      analyzed using amino acid sequences of 25 therapeutic antibodies, 55 TcIEs 
      recognized by T-regulatory cells (tregitopes), 1000 randomly generated 
      15-residue-long peptides, 2257 human self-TcIEs (autoantigens), and 11 peptides 
      in HLA-peptide cocrystal structures. Sequence analyses from these diverse sources 
      consistently show a high level of correlation between APRs and TcIEs: 
      approximately one-third of TcIEs contain APRs, but the majority of APRs occur 
      within TcIE regions (TcIERs). Tregitopes also contain APRs. Most APR-containing 
      TcIERs can bind multiple HLA-DR alleles, suggesting that aggregation-driven 
      adverse immune responses could impact a broad segment of patient population. This 
      article has identified common molecular sequence-structure loci that potentially 
      contribute toward both manufacturability and safety profiles of the therapeutic 
      antibodies, thereby laying a foundation for simultaneous optimization of these 
      attributes in novel and follow-on candidates. Incidence of APRs within TcIERs is 
      not special to biotherapeutics, self-TcIEs from human proteins, involved in 
      various diseases, also contain predicted APRs and experimentally proven 
      amyloid-fibril-forming peptide sequence portions.
CI  - Copyright (c) 2012 Wiley Periodicals, Inc.
FAU - Kumar, Sandeep
AU  - Kumar S
AD  - Biotherapeutics Pharmaceutical Sciences Research and Development, Pfizer Inc., 
      Chesterfield, Missouri 63017, USA. Sandeep.Kumar@Pfizer.com
FAU - Mitchell, Mark A
AU  - Mitchell MA
FAU - Rup, Bonita
AU  - Rup B
FAU - Singh, Satish K
AU  - Singh SK
LA  - eng
PT  - Journal Article
DEP - 20120522
PL  - United States
TA  - J Pharm Sci
JT  - Journal of pharmaceutical sciences
JID - 2985195R
RN  - 0 (Amyloid)
RN  - 0 (Antibodies)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (Peptides)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amyloid/chemistry/*immunology
MH  - Antibodies/chemistry/*immunology/*therapeutic use
MH  - Computer-Aided Design
MH  - *Drug Design
MH  - Epitopes, T-Lymphocyte/*immunology
MH  - HLA-DR Antigens/*immunology
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Peptides/chemistry/immunology/therapeutic use
MH  - Sequence Alignment
EDAT- 2012/05/24 06:00
MHDA- 2012/10/23 06:00
CRDT- 2012/05/24 06:00
PHST- 2012/01/26 00:00 [received]
PHST- 2012/03/21 00:00 [revised]
PHST- 2012/04/06 00:00 [accepted]
PHST- 2012/05/24 06:00 [entrez]
PHST- 2012/05/24 06:00 [pubmed]
PHST- 2012/10/23 06:00 [medline]
AID - S0022-3549(15)31474-X [pii]
AID - 10.1002/jps.23169 [doi]
PST - ppublish
SO  - J Pharm Sci. 2012 Aug;101(8):2686-701. doi: 10.1002/jps.23169. Epub 2012 May 22.