PMID- 29545330
OWN - NLM
STAT- MEDLINE
DCOM- 20190708
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Print)
IS  - 1535-7163 (Linking)
VI  - 17
IP  - 5
DP  - 2018 May
TI  - Potent Immune Modulation by MEDI6383, an Engineered Human OX40 Ligand IgG4P Fc 
      Fusion Protein.
PG  - 1024-1038
LID - 10.1158/1535-7163.MCT-17-0200 [doi]
AB  - Ligation of OX40 (CD134, TNFRSF4) on activated T cells by its natural ligand 
      (OX40L, CD252, TNFSF4) enhances cellular survival, proliferation, and effector 
      functions such as cytokine release and cellular cytotoxicity. We engineered a 
      recombinant human OX40L IgG4P Fc fusion protein termed MEDI6383 that assembles 
      into a hexameric structure and exerts potent agonist activity following 
      engagement of OX40. MEDI6383 displayed solution-phase agonist activity that was 
      enhanced when the fusion protein was clustered by Fc gamma receptors (FcgammaRs) on 
      the surface of adjacent cells. The resulting costimulation of OX40 on T cells 
      induced NFkappaB promoter activity in OX40-expressing T cells and induced Th1-type 
      cytokine production, proliferation, and resistance to regulatory T cell 
      (Treg)-mediated suppression. MEDI6383 enhanced the cytolytic activity of 
      tumor-reactive T cells and reduced tumor growth in the context of an alloreactive 
      human T cell:tumor cell admix model in immunocompromised mice. Consistent with 
      the role of OX40 costimulation in the expansion of memory T cells, MEDI6383 
      administered to healthy nonhuman primates elicited peripheral blood CD4 and CD8 
      central and effector memory T-cell proliferation as well as B-cell proliferation. 
      Together, these results suggest that OX40 agonism has the potential to enhance 
      antitumor immunity in human malignancies. Mol Cancer Ther; 17(5); 1024-38. (c)2018 
      AACR.
CI  - (c)2018 American Association for Cancer Research.
FAU - Oberst, Michael D
AU  - Oberst MD
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Auge, Catherine
AU  - Auge C
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Morris, Chad
AU  - Morris C
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Kentner, Stacy
AU  - Kentner S
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Mulgrew, Kathy
AU  - Mulgrew K
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - McGlinchey, Kelly
AU  - McGlinchey K
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Hair, James
AU  - Hair J
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Hanabuchi, Shino
AU  - Hanabuchi S
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland.
FAU - Du, Qun
AU  - Du Q
AD  - Department of Antibody Development and Protein Engineering, MedImmune, 
      Gaithersburg, Maryland.
FAU - Damschroder, Melissa
AU  - Damschroder M
AD  - Department of Antibody Development and Protein Engineering, MedImmune, 
      Gaithersburg, Maryland.
FAU - Feng, Hui
AU  - Feng H
AD  - Department of Antibody Development and Protein Engineering, MedImmune, 
      Gaithersburg, Maryland.
FAU - Eck, Steven
AU  - Eck S
AD  - Translational Science, MedImmune, Gaithersburg, Maryland.
FAU - Buss, Nicholas
AU  - Buss N
AD  - Department of Toxicology, MedImmune, Gaithersburg, Maryland.
FAU - de Haan, Lolke
AU  - de Haan L
AD  - Department of Toxicology, MedImmune, Gaithersburg, Maryland.
FAU - Pierce, Andrew J
AU  - Pierce AJ
AD  - Innovative Medicines, Oncology, AstraZeneca, Cambridge, United Kingdom.
FAU - Park, Haesun
AU  - Park H
AD  - Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and 
      Pathology, and the Oregon National Primate Research Center, Oregon Health & 
      Science University, Beaverton, Oregon.
FAU - Sylwester, Andrew
AU  - Sylwester A
AD  - Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and 
      Pathology, and the Oregon National Primate Research Center, Oregon Health & 
      Science University, Beaverton, Oregon.
FAU - Axthelm, Michael K
AU  - Axthelm MK
AD  - Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and 
      Pathology, and the Oregon National Primate Research Center, Oregon Health & 
      Science University, Beaverton, Oregon.
FAU - Picker, Louis
AU  - Picker L
AD  - Vaccine and Gene Therapy Institute, Departments of Molecular Microbiology and 
      Pathology, and the Oregon National Primate Research Center, Oregon Health & 
      Science University, Beaverton, Oregon.
FAU - Morris, Nicholas P
AU  - Morris NP
AD  - Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon.
AD  - AgonOx, Portland, Oregon.
FAU - Weinberg, Andrew
AU  - Weinberg A
AD  - Earle A. Chiles Research Institute, Providence Cancer Center, Portland, Oregon.
AD  - AgonOx, Portland, Oregon.
FAU - Hammond, Scott A
AU  - Hammond SA
AD  - Department of Oncology Research, MedImmune, Gaithersburg, Maryland. 
      hammonds@medimmune.com.
LA  - eng
GR  - P51 OD011092/OD/NIH HHS/United States
GR  - U42 OD010426/OD/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180315
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Cytokines)
RN  - 0 (Immunoglobulin Fc Fragments)
RN  - 0 (Immunoglobulin G)
RN  - 0 (OX40 Ligand)
RN  - 0 (Receptors, OX40)
RN  - 0 (Recombinant Fusion Proteins)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cytokines/immunology/metabolism
MH  - Cytotoxicity, Immunologic/drug effects/immunology
MH  - Female
MH  - HEK293 Cells
MH  - Humans
MH  - Immunoglobulin Fc Fragments/genetics/*immunology/metabolism
MH  - Immunoglobulin G/genetics/*immunology/metabolism
MH  - Lymphocyte Activation/drug effects/immunology
MH  - Macaca mulatta
MH  - OX40 Ligand/genetics/*immunology/metabolism
MH  - Protein Multimerization/immunology
MH  - Receptors, OX40/agonists/immunology/metabolism
MH  - Recombinant Fusion Proteins/chemistry/*immunology/pharmacology
MH  - T-Lymphocytes/immunology/metabolism
MH  - T-Lymphocytes, Regulatory/immunology/metabolism
PMC - PMC5932227
MID - NIHMS944700
COIS- Conflicts of interest/Financial Disclosure: Michael Oberst, Catherine Auge, Chad 
      Morris, Stacy Kentner, Kathy Mulgrew, Kelly McGlinchey, James Hair, Shino 
      Hanabuchi, Qun Du, Melissa Damschroder, Hui Feng, Steven Eck, Nicholas Buss, 
      Lolke de Haan, Andrew Pierce, and Scott Hammond are/were employees of 
      AstraZeneca/MedImmune. Nicholas Morris and Andrew Weinberg are employees of 
      AgonOx. Haesun Park, Andrew Sylwester, Michael Axthelm, and Louis Picker have no 
      conflicts of interest.
EDAT- 2018/03/17 06:00
MHDA- 2019/07/10 06:00
PMCR- 2019/05/01
CRDT- 2018/03/17 06:00
PHST- 2017/03/06 00:00 [received]
PHST- 2017/08/11 00:00 [revised]
PHST- 2018/02/12 00:00 [accepted]
PHST- 2018/03/17 06:00 [pubmed]
PHST- 2019/07/10 06:00 [medline]
PHST- 2018/03/17 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - 1535-7163.MCT-17-0200 [pii]
AID - 10.1158/1535-7163.MCT-17-0200 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2018 May;17(5):1024-1038. doi: 10.1158/1535-7163.MCT-17-0200. 
      Epub 2018 Mar 15.