PMID- 20682652
OWN - NLM
STAT- MEDLINE
DCOM- 20101126
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 9
IP  - 8
DP  - 2010 Aug
TI  - Decreased survival of human breast cancer cells expressing HER2/neu on in vitro 
      incubation with an anti-HER2/neu antibody fused to C5a or C5a desArg.
PG  - 2175-85
LID - 10.1158/1535-7163.MCT-09-1054 [doi]
AB  - Treatment of human epidermal growth factor receptor 2 (HER2/neu)-expressing 
      breast cancer patients with a monoclonal antibody (mAb) directed against HER2/neu 
      improves the outcome of chemotherapy. In cases in which remission is observed, 
      antibody-dependent cell-mediated cytotoxicity (ADCC) seems to be one of the main 
      mechanisms of anti-HER2/neu mAb action, implicating Fc gamma receptors (Fc gamma 
      Rs) in this tumoricidal activity. In vitro and in vivo studies have revealed that 
      anti-HER2/neu-mediated ADCC is mainly accomplished by polymorphonuclear 
      granulocytes (PMN). C5a, a cleavage product of the complement component C5, 
      modulates Fc gamma R expression via upregulation of activating and downregulation 
      of inhibitory Fc gamma Rs. C5a also recruits PMNs to sites of inflammation and 
      increases PMN survival. To enhance the recruitment and activation of C5a 
      receptor-bearing cells into the tumor microenvironment, we developed antibody 
      fusion proteins composed of a human IgG3 anti-HER2/neu antibody genetically fused 
      to C5a [anti-HER2/neu IgG3-(C5a)] or to its derivative, C5a(desArg) 
      [anti-HER2/neu IgG3-(C5a(desArg))]. Both fusion proteins were expressed, properly 
      assembled, and secreted by murine myeloma cells, and displayed chemotactic 
      activity on human PMN. Under comparable conditions, anti-HER2/neu 
      IgG3-(C5a(desArg)) increased the survival of PMN more efficiently than 
      anti-HER2/neu IgG3-(C5a) or C5a(desArg). Surprisingly, incubation of the fusion 
      proteins with breast cancer cells that overexpress HER2/neu (SK-BR-3) induced 
      cell death at a dose at which the anti-HER2/neu IgG3 antibody was innocuous. In 
      the presence of human peripheral blood leukocytes as effector cells, both fusion 
      proteins induced tumor cell death more efficiently than anti-HER2/neu IgG3. These 
      data suggest that anti-HER2/neu IgG3-(C5a) and anti-HER2/neu IgG3-(C5a(desArg)) 
      fusion proteins possess novel properties that could be useful in cancer 
      immunotherapy.
CI  - (c) 2010 AACR.
FAU - Fuenmayor, Jaheli
AU  - Fuenmayor J
AD  - Laboratorio de Patologia Celular y Molecular, Centro de Medicina Experimental, 
      Instituto Venezolano de Investigaciones Cientificas, Apartado 20632, Caracas 
      1020-A, Venezuela. jfuenmay@ivic.gob.ve
FAU - Perez-Vazquez, Karin
AU  - Perez-Vazquez K
FAU - Perez-Witzke, Daniel
AU  - Perez-Witzke D
FAU - Penichet, Manuel L
AU  - Penichet ML
FAU - Montano, Ramon F
AU  - Montano RF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100803
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Complement C5a, des-Arginine)
RN  - 0 (Receptor, Anaphylatoxin C5a)
RN  - 0 (Receptors, IgG)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 80295-54-1 (Complement C5a)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Antibodies, Monoclonal/*immunology/metabolism
MH  - Antibody-Dependent Cell Cytotoxicity
MH  - Breast Neoplasms/immunology/*metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Cell Survival
MH  - Chemotaxis, Leukocyte
MH  - Complement C5a/*metabolism
MH  - Complement C5a, des-Arginine/*metabolism
MH  - Female
MH  - Humans
MH  - Neutrophil Activation
MH  - Protein Binding
MH  - Receptor, Anaphylatoxin C5a/metabolism
MH  - Receptor, ErbB-2/immunology/*metabolism
MH  - Receptors, IgG/metabolism
MH  - Recombinant Fusion Proteins/chemistry/*metabolism
EDAT- 2010/08/05 06:00
MHDA- 2010/12/14 06:00
CRDT- 2010/08/05 06:00
PHST- 2010/08/05 06:00 [entrez]
PHST- 2010/08/05 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
AID - 1535-7163.MCT-09-1054 [pii]
AID - 10.1158/1535-7163.MCT-09-1054 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2010 Aug;9(8):2175-85. doi: 10.1158/1535-7163.MCT-09-1054. Epub 
      2010 Aug 3.