PMID- 29296968
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221109
IS  - 2473-9529 (Print)
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Linking)
VI  - 1
IP  - 8
DP  - 2017 Mar 14
TI  - A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated 
      cytotoxicity and induces iC3b.
PG  - 504-515
LID - 10.1182/bloodadvances.2016001917 [doi]
AB  - GL-2045 is a recombinant human immunoglobulin G1 (IgG1)-based Fc multimer 
      designed to recapitulate the anti-inflammatory activities of intravenous 
      immunoglobulin (IVIG) on the innate and adaptive immune responses. We used 
      functional in vitro studies to determine if GL-2045 could mimic the modulatory 
      activity of IVIG on complement activation. GL-2045, at log-order lower 
      concentrations than heat-aggregated IgG (HAGG) and IVIG, protected 
      antibody-opsonized cells from complement-dependent cytotoxicity. These protective 
      effects were completely mediated by the higher order multimer fractions of 
      GL-2045 and were partially dependent upon sequestration of C1q. Exposure of serum 
      to GL-2045 and, to a lesser extent, IVIG, resulted in high levels of C4a, limited 
      levels of C3a, and no C5a. In contrast, HAGG induced high levels of C4a, C3a, and 
      C5a. The means by which GL-2045 governed complement activation was dependent on 
      its ability to augment the function of factor H, alone and in combination with 
      factor I, to indirectly limit the alternative form of C3 convertase, with 
      resultant increases in the anti-inflammatory molecule, the "inactive" form of 
      C3b, called iC3b. Although IVIG, like GL-2045, potentiated factor H function, it 
      also directly inhibited the alternative form of C3 convertase. Our findings help 
      elucidate how IVIG, GL-2045, and HAGG regulate complement function. Furthermore, 
      the capacity of GL-2045 to sequester C1q and augment factor H activity, in 
      combination with its ability to generate activation-induced immunomodulatory 
      complement split products, such as iC3b, make it a viable drug candidate for the 
      treatment of diverse complement-mediated diseases.
FAU - Zhou, Hua
AU  - Zhou H
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland 
      School of Medicine, Baltimore, MD.
FAU - Olsen, Henrik
AU  - Olsen H
AD  - Gliknik Inc., Baltimore, MD; and.
FAU - So, Edward
AU  - So E
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland 
      School of Medicine, Baltimore, MD.
FAU - Merigeon, Emmanuel
AU  - Merigeon E
AD  - Gliknik Inc., Baltimore, MD; and.
FAU - Rybin, Denis
AU  - Rybin D
AD  - Pfizer Inc., Boston, MA.
FAU - Owens, Jane
AU  - Owens J
AD  - Pfizer Inc., Boston, MA.
FAU - LaRosa, Gregory
AU  - LaRosa G
AD  - Pfizer Inc., Boston, MA.
FAU - Block, David S
AU  - Block DS
AD  - Gliknik Inc., Baltimore, MD; and.
FAU - Strome, Scott E
AU  - Strome SE
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland 
      School of Medicine, Baltimore, MD.
FAU - Zhang, Xiaoyu
AU  - Zhang X
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland 
      School of Medicine, Baltimore, MD.
LA  - eng
PT  - Journal Article
DEP - 20170314
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
PMC - PMC5728453
COIS- Conflict-of-interest disclosure: S.E.S. is a cofounder, consultant, and 
      stockholder in Gliknik Inc, a biotechnology company. He receives royalties for 
      intellectual property, related to B7-H1 (PD-L1), licensed by the Mayo Clinic 
      College of Medicine to third parties. He is a paid consultant to Astra Zeneca. He 
      also receives research support from Pfizer and Gliknik through sponsored research 
      agreements through the University of Maryland, Baltimore. D.S.B. is cofounder of 
      Gliknik Inc. and an employee. H.O. and E.M. are employees of Gliknik. D.R., J.O., 
      and G.L. are employees of Pfizer Inc.
EDAT- 2018/01/04 06:00
MHDA- 2018/01/04 06:01
PMCR- 2017/03/14
CRDT- 2018/01/04 06:00
PHST- 2016/10/07 00:00 [received]
PHST- 2017/02/15 00:00 [accepted]
PHST- 2018/01/04 06:00 [entrez]
PHST- 2018/01/04 06:00 [pubmed]
PHST- 2018/01/04 06:01 [medline]
PHST- 2017/03/14 00:00 [pmc-release]
AID - 2016/001917 [pii]
AID - 10.1182/bloodadvances.2016001917 [doi]
PST - epublish
SO  - Blood Adv. 2017 Mar 14;1(8):504-515. doi: 10.1182/bloodadvances.2016001917. 
      eCollection 2017 Mar 14.