PMID- 36945694
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230328
IS  - 2674-0338 (Electronic)
IS  - 2674-0338 (Linking)
VI  - 2
DP  - 2022
TI  - In silico Immunogenicity Assessment for Sequences Containing Unnatural Amino 
      Acids: A Method Using Existing in silico Algorithm Infrastructure and a Vision 
      for Future Enhancements.
LID - 952326 [pii]
LID - 10.3389/fddsv.2022.952326 [doi]
AB  - The in silico prediction of T cell epitopes within any peptide or biologic drug 
      candidate serves as an important first step for assessing immunogenicity. T cell 
      epitopes bind human leukocyte antigen (HLA) by a well-characterized interaction 
      of amino acid side chains and pockets in the HLA molecule binding groove. 
      Immunoinformatics tools, such as the EpiMatrix algorithm, have been developed to 
      screen natural amino acid sequences for peptides that will bind HLA. In addition 
      to commonly occurring in synthetic peptide impurities, unnatural amino acids 
      (UAA) are also often incorporated into novel peptide therapeutics to improve 
      properties of the drug product. To date, the HLA binding properties of peptides 
      containing UAA are not accurately estimated by most algorithms. Both scenarios 
      warrant the need for enhanced predictive tools. The authors developed an in 
      silico method for modeling the impact of a given UAA on a peptide's likelihood of 
      binding to HLA and, by extension, its immunogenic potential. In silico assessment 
      of immunogenic potential allows for risk-based selection of best candidate 
      peptides in further confirmatory in vitro, ex vivo and in vivo assays, thereby 
      reducing the overall cost of immunogenicity evaluation. Examples demonstrating in 
      silico immunogenicity prediction for product impurities that are commonly found 
      in formulations of the generic peptides teriparatide and semaglutide are 
      provided. Next, this article discusses how HLA binding studies can be used to 
      estimate the binding potentials of commonly encountered UAA and "correct" in 
      silico estimates of binding based on their naturally occurring counterparts. As 
      demonstrated here, these in vitro binding studies are usually performed with 
      known ligands which have been modified to contain UAA in HLA anchor positions. An 
      example using D-amino acids in relative binding position 1 (P1) of the PADRE 
      peptide is presented. As more HLA binding data become available, new predictive 
      models allowing for the direct estimation of HLA binding for peptides containing 
      UAA can be established.
FAU - Mattei, Aimee E
AU  - Mattei AE
AD  - EpiVax, Inc., Providence, RI, United States.
FAU - Gutierrez, Andres H
AU  - Gutierrez AH
AD  - EpiVax, Inc., Providence, RI, United States.
FAU - Martin, William D
AU  - Martin WD
AD  - EpiVax, Inc., Providence, RI, United States.
FAU - Terry, Frances E
AU  - Terry FE
AD  - EpiVax, Inc., Providence, RI, United States.
FAU - Roberts, Brian J
AU  - Roberts BJ
AD  - EpiVax, Inc., Providence, RI, United States.
FAU - Rosenberg, Amy S
AU  - Rosenberg AS
AD  - EpiVax, Inc., Providence, RI, United States.
FAU - De Groot, Anne S
AU  - De Groot AS
AD  - EpiVax, Inc., Providence, RI, United States.
LA  - eng
GR  - 75F40120C00157/ImFDA/Intramural FDA HHS/United States
PT  - Journal Article
DEP - 20221010
PL  - Switzerland
TA  - Front Drug Discov (Lausanne)
JT  - Frontiers in drug discovery
JID - 9918350785506676
PMC - PMC10026553
MID - NIHMS1854666
OTO - NOTNLM
OT  - D-amino acid
OT  - HLA binding
OT  - Immunogenicity
OT  - Immunoinformatic analysis
OT  - Impurity
OT  - Peptide Drug
OT  - T cell epitope
OT  - unnatural amino acid (UAA)
COIS- Conflict of interest AD and WM are senior officer and shareholders, and AM, AG, 
      BR, FT, and AR are employees of EpiVax, Inc., a privately owned biotechnology 
      company located in Providence, RI.
EDAT- 2022/01/01 00:00
MHDA- 2022/01/01 00:01
PMCR- 2023/03/20
CRDT- 2023/03/22 01:59
PHST- 2023/03/22 01:59 [entrez]
PHST- 2022/01/01 00:00 [pubmed]
PHST- 2022/01/01 00:01 [medline]
PHST- 2023/03/20 00:00 [pmc-release]
AID - 952326 [pii]
AID - 10.3389/fddsv.2022.952326 [doi]
PST - ppublish
SO  - Front Drug Discov (Lausanne). 2022;2:952326. doi: 10.3389/fddsv.2022.952326. Epub 
      2022 Oct 10.