Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo

  title={Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo},
  author={Nai‐Kong V. Cheung and Hong-fen Guo and Jian Hu and Dimiter V. Tassev and Irene Y Cheung},
  pages={477 - 486}
Murine IgG3 anti-GD2 antibody m3F8 has shown anti-neuroblastoma activity in Phase I/II studies, where antibody-dependent cell-mediated cytotoxicity (ADCC) played a key role. Humanization of m3F8 should circumvent human anti-mouse antibody (HAMA) response and enhance its ADCC properties to reduce dosing and pain side effect. Chimeric 3F8 (ch3F8) and humanized 3F8 (hu3F8-IgG1 and hu3F8-IgG4) were produced and purified by protein A affinity chromatography. In vitro comparison was made with m3F8… 
Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3*
The molecular epitope of 8H9 was determined to be dependent on the FG loop of B7-H3, a region critical to its function in immunologic blockade and unique among anti-B7- H3 antibodies published to date.
Antitumor Efficacy of Anti-GD2 IgG1 Is Enhanced by Fc Glyco-Engineering
A potent ADCC-enhanced antibody is described that, in comparison with Abs with altered affinities for Fc receptors, significantly improved the growth control of tumors expressing cancer-antigen GD2.
Chimeric Antibody c.8B6 to O-Acetyl-GD2 Mediates the Same Efficient Anti-Neuroblastoma Effects as Therapeutic ch14.18 Antibody to GD2 without Antibody Induced Allodynia
It is found that antibody c.8B6 shares the same anti-neuroblastoma attributes as therapeutic ch14.18 anti-GD2 mAb when tested in cell-based assay and in vivo in an animal model.
Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody
The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells.
Anti-proliferative and pro-apoptotic activity of GD2 ganglioside-specific monoclonal antibody 3F8 in human melanoma cells
Results indicated that multiple mechanisms played a role in the antitumor activity of mAb 3F8 in melanoma cells, which should provide a mechanistic basis for the optimization of the rational design of immunotherapeutic strategies in the mAb-based treatment of GD2 positive tumors.
Preclinical Evaluation of Multistep Targeting of Diasialoganglioside GD2 Using an IgG-scFv Bispecific Antibody with High Affinity for GD2 and DOTA Metal Complex
It is concluded that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate subcutaneous GD2(+)-NB in mice while sparing kidney and bone marrow.
Humanized 3F8 Anti-GD2 Monoclonal Antibody Dosing With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Resistant Neuroblastoma: A Phase 1 Clinical Trial
This phase 1 clinical trial found hu3F8 to be associated with modest toxic effects, low immunogenicity, and substantial antineuroblastoma activity; phase 2 trials are in progress.
Humanization of high-affinity antibodies targeting glypican-3 in hepatocellular carcinoma
This study successfully humanizes and validates high affinity anti-GPC3 antibodies and sets a foundation for future development of these antibodies in various clinical formats in the treatment of liver cancer.
Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival
It is concluded that hu3F8 had low immunogenicity, which was prognostic of progression-free survival and overall survival in stage 4 patients with refractory/relapsed neuroblastoma.
High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model
The fatal neurotoxicity of GD2-specific CAR T-cell therapy observed in these studies suggests that GD2 may be a difficult target antigen forCAR T- cell therapy without additional strategies that can control CART-cell function within the CNS.


Enhancement of antibody-dependent cytotoxicity with a chimeric anti-GD2 antibody.
A mouse/human chimeric antibody was developed that reacts with the disialoganglioside GD2 on the surface of tumor cells of neuroectodermal origin that causes cytotoxicity of human effector cells against melanoma cells 50- to 100-fold more efficiently than 14.G2a-activated human C-mediated cytolysis of melanoma cell.
Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors
The data suggest that, for mouse IgG3, the rat may provide a more relevant rodent model than the mouse for testing the in vivo antitumor effects of monoclonal antibodies.
Functional properties and effect on growth suppression of human neuroblastoma tumors by isotype switch variants of monoclonal antiganglioside GD2 antibody 14.18.
These studies suggest that a mechanism(s) other than Fc-directed complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxic effects may account for the in vivo antitumor effects of these particular antibodies.
Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model.
It is shown that complement depletion enhances NK-cell activation induced by rituximab-coated target cells and improves the efficacy of mAb therapy in a murine lymphoma model.
Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children's Cancer Group Study.
  • M. Ozkaynak, P. Sondel, R. Seeger
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2000
Ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities, and three dose-limiting toxicities were observed among six patients at 50 mg/m(2)/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting.
Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells.
An anti-GD2 ganglioside human/mouse chimeric monoclonal antibody, ch14.18, was shown to bind to human neuroblastoma cells, and granulocytes were effective in mediating lysis of neuro Blastoma cells coated with ch 14.18 irrespective of whether they were obtained from normal adults or from neuroblastomas patients.
Absolute requirement of CD11/CD18 adhesion molecules, FcRII and the phosphatidylinositol-linked FcRIII for monoclonal antibody-mediated neutrophil antihuman tumor cytotoxicity.
Optimal ADCC using human PMN, human solid tumor cells, and a clinically active MoAb (conditions that contrast with the heterologous antibodies and nonhuman or nonneoplastic targets used in most models of PMN ADCC) required CD11b, CD11c, FcRII, and the PI-linked F cRIII.
Reducing Epitope Spread during Affinity Maturation of an Anti-Ganglioside GD2 Antibody1
It is concluded that epitope spread during affinity maturation can be reduced by negative selection, and efficiency of the negative selector depends on its cross-reactive affinity with the matured scFv.
Immunogenicity of the Hu14.18-IL2 Immunocytokine Molecule in Adults With Melanoma and Children With Neuroblastoma
There was a positive correlation between the peak serum level of IC in course 1 and the anti–Fc-IL2 response, indicating that development of anti-idiotypic antibodies interfered with detection of circulating hu14.18- IL2.
FCGR2A polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor.
The favorable outcome associated with FCGR2A (R/R) genotype is consistent with the proposed role of FC GR2A and phagocyte-mediated ADCC in 3F8 plus GM-CSF immunotherapy.