PMID- 35760121
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20220930
IS  - 1520-6017 (Electronic)
IS  - 0022-3549 (Linking)
VI  - 111
IP  - 9
DP  - 2022 Sep
TI  - Effect of the ADCC-Modulating Mutations and the Selection of Human IgG Isotypes 
      on Physicochemical Properties of Fc.
PG  - 2411-2421
LID - S0022-3549(22)00261-1 [pii]
LID - 10.1016/j.xphs.2022.06.014 [doi]
AB  - Monoclonal antibodies, particularly IgGs and Ig-based molecules, are a 
      well-established and growing class of biotherapeutic drugs. In order to improve 
      efficacy, potency and pharmacokinetics of these therapeutic drugs, pharmaceutical 
      industries have investigated significantly in engineering fragment crystallizable 
      (Fc) domain of these drugs to optimize the interactions of these drugs and Fc 
      gamma receptors (FcgammaRs) in recent ten years. The biological function of the 
      therapeutics with the antibody-dependent cellular cytotoxicity (ADCC) enhanced 
      double mutation (S239D/I332E) of isotype IgG1, the ADCC reduced double mutation 
      (L234A/L235A) of isotype IgG1, and ADCC reduced isotype IgG4 has been well 
      understood. However, limited information regarding the effect of these mutations 
      or isotype difference on physicochemical properties (PCP), developability, and 
      manufacturability of therapeutics bearing these different Fc regions is 
      available. In this report, we systematically characterize the effects of the 
      mutations and IgG4 isotype on conformation stability, colloidal stability, 
      solubility, and storage stability at accelerated conditions in two buffer systems 
      using six Fc variants. Our results provide a basis for selecting appropriate Fc 
      region during development of IgG or Ig-based therapeutics and predicting effect 
      of the mutations on CMC development process.
CI  - Copyright (c) 2022 American Pharmacists Association. Published by Elsevier Inc. All 
      rights reserved.
FAU - Wu, Helen Haixia
AU  - Wu HH
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA. Electronic address: 
      helen.wu@boehringer-ingelheim.com.
FAU - Crames, Maureen
AU  - Crames M
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Wei, Yangjie
AU  - Wei Y
AD  - Amgen Inc., Drug Product Technologies, Thousand Oaks, CA, USA.
FAU - Liu, Dongmei
AU  - Liu D
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Gueneva-Boucheva, Kristina
AU  - Gueneva-Boucheva K
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Son, Ikbae
AU  - Son I
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Frego, Lee
AU  - Frego L
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Han, Fei
AU  - Han F
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Kroe-Barrett, Rachel
AU  - Kroe-Barrett R
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Nixon, Andrew
AU  - Nixon A
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
FAU - Marlow, Michael
AU  - Marlow M
AD  - Boehringer Ingelheim Pharmaceuticals Inc., Innovation Unit, Biotherapeutics 
      Discovery, Ridgefield, CT, USA.
LA  - eng
PT  - Journal Article
DEP - 20220626
PL  - United States
TA  - J Pharm Sci
JT  - Journal of pharmaceutical sciences
JID - 2985195R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Immunoglobulin Fc Fragments)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, IgG)
SB  - IM
MH  - Antibodies, Monoclonal/chemistry
MH  - *Antibody-Dependent Cell Cytotoxicity/genetics
MH  - Humans
MH  - Immunoglobulin Fc Fragments/chemistry/genetics
MH  - Immunoglobulin G/chemistry
MH  - Mutation
MH  - *Receptors, IgG/chemistry/genetics
OTO - NOTNLM
OT  - ADCC
OT  - Effector function
OT  - Fc engineering
OT  - IgG
OT  - Monoclonal antibodies
OT  - Protein aggregation
OT  - Protein stability
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2022/06/28 06:00
MHDA- 2022/08/23 06:00
CRDT- 2022/06/27 19:23
PHST- 2022/05/24 00:00 [received]
PHST- 2022/06/19 00:00 [revised]
PHST- 2022/06/20 00:00 [accepted]
PHST- 2022/06/28 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/06/27 19:23 [entrez]
AID - S0022-3549(22)00261-1 [pii]
AID - 10.1016/j.xphs.2022.06.014 [doi]
PST - ppublish
SO  - J Pharm Sci. 2022 Sep;111(9):2411-2421. doi: 10.1016/j.xphs.2022.06.014. Epub 
      2022 Jun 26.