High-avidity human IgGκ monoclonal antibodies from a novel strain of minilocus transgenic mice

Fishwild, Dianne M.; O'Donnell, Susan L.; Bengoechea, Tasha; Hudson, Debra V.; Harding, Fiona; Bernhard, Susan L.; Jones, Deborah; Kay, Robert M.; Higgins, Kay M.; Schramm, Stephen R.; Lönberg, Nils

doi:10.1038/nbt0796-845

Cited by 253 publications

(146 citation statements)

References 49 publications

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“…Two peptides from protease-treated human PD-1, 29 SFVLNWYR-MSPSNQTDKLAAF-PEDR 53 (putative glycosylation site underlined) and 85 SGTYLC-GAISLAPKAQIKE 103 , bound to nivolumab (Supplementary Fig. S2A).…”

Section: Binding Analysis Of Nivolumab and Inhibition Of Ligand Bindingmentioning

confidence: 99%

“…Transgenic mice comprising germline configuration human immunoglobulin miniloci in an endogenous IgH and Igk knockout background (28,29) were used to generate human anti-PD-1 monoclonal antibodies (mAb). The transgenic mice were immunized with recombinant human PD-1-Fc protein consisting of the extracellular domain of PD-1 (amino acids 1-167) and the Fc portion of human IgG1, and Chinese hamster ovary (CHO) cells expressing human PD-1 (CHO-PD-1 cells).…”

Section: Antibody Generationmentioning

confidence: 99%

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In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

Wang

Thudium

Han

et al. 2014

Cancer Immunology Research

514

405

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The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, limiting bystander tissue damage and preventing the development of autoimmunity during inflammatory responses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions upon binding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, the expression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor and immune cells in the tumor microenvironment undermine antitumor immunity and support its rationale for PD-1 blockade in cancer immunotherapy. This report details the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumab binds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicity was observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did not induce adverse immune-related events when given to cynomolgus macaques at high concentrations, independent of circulating anti-nivolumab antibodies where observed. These data provide a comprehensive preclinical characterization of nivolumab, for which antitumor activity and safety have been demonstrated in human clinical trials in various solid tumors. Cancer Immunol Res; 2(9); 846-56. Ó2014 AACR.

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Section: Binding Analysis Of Nivolumab and Inhibition Of Ligand Bindingmentioning

confidence: 99%

Section: Antibody Generationmentioning

confidence: 99%

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

Wang

Thudium

Han

et al. 2014

Cancer Immunology Research

514

405

View full text Add to dashboard Cite

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“…Human IgG1K monoclonal antibodies were generated in human antibody transgenic mice; HuMAb mice (Medarex), using hybridoma technology (21). TF antibodies were previously described (4).…”

Section: Antibody Generation and Conjugationmentioning

confidence: 99%

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Goeij

Satijn

Freitag

et al. 2015

Molecular Cancer Therapeutics

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Antibody-drug conjugates (ADC) are emerging as powerful cancer treatments that combine antibody-mediated tumor targeting with the potent cytotoxic activity of toxins. We recently reported the development of a novel ADC that delivers the cytotoxic payload monomethyl auristatin E (MMAE) to tumor cells expressing tissue factor (TF). By carefully selecting a TFspecific antibody that interferes with TF:FVIIa-dependent intracellular signaling, but not with the procoagulant activity of TF, an ADC was developed (TF-011-MMAE/HuMax-TF-ADC) that efficiently kills tumor cells, with an acceptable toxicology profile. To gain more insight in the efficacy of TF-directed ADC treatment, we compared the internalization characteristics and intracellular routing of TF with the EGFR and HER2. Both in absence and presence of antibody, TF demonstrated more efficient internalization, lysosomal targeting, and degradation than EGFR and HER2. By conjugating TF, EGFR, and HER2-specific antibodies with duostatin-3, a toxin that induces potent cytotoxicity upon antibody-mediated internalization but lacks the ability to induce bystander killing, we were able to compare cytotoxicity of ADCs with different tumor specificities. TF-ADC demonstrated effective killing against tumor cell lines with variable levels of target expression. In xenograft models, TF-ADC was relatively potent in reducing tumor growth compared with EGFR-and HER2-ADCs. We hypothesize that the constant turnover of TF on tumor cells makes this protein specifically suitable for an ADC approach.

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“…The HuMab mouse (GenPharm, Canada) with four distinct genetic modifications [391]: (1) deletion of the endogenous H-chain J gene segments preventing VDJ rearrangement and expression of murine IgM; (2) deletion of the κL-chain J and C segments; (3) transgenic for a human-heavy chain minilocus containing 4 V H gene segments, 16 D segments, 6 J H segments, C μ and C γ 1; (4) combination of plasmids and a 450-kilobase yeast artificial chromosome (YAC) comprising most V k sequences, V H sequences as well as all 5 J k and C k .…”

Section: Fully Human Mabsmentioning

confidence: 99%

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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This report discusses the history and mechanisms of vaccination of humans as well as the engineering of therapeutic antibodies. Deeper understanding of the molecular interactions involved in both acquired and innate immunity is allowing sophistication in design of modified and even synthetic vaccines. Recombinant DNA technologies are facilitating development of DNA-based vaccines, for example, with the recognition that unmethylated CpG sequences in plasmid DNA will target Toll-like receptors on antigen-presenting cells. Formulations of DNA vaccines with increased immunogenicity include engineering into plasmids with "genetic adjuvant" capability, incorporation into polymeric or magnetic nanoparticles, and formulation with cationic polymers and other polymeric and non-polymeric coatings. Newer methods of delivery, such as particle bombardment, DNA tattooing, electroporation, and magnetic delivery, are also improving the effectiveness of DNA vaccines. RNA-based vaccines and reverse vaccinology based on gene sequencing and bioinformatic approaches are also considered. Structural vaccinology is an approach in which the detailed molecular structure of viral epitopes is used to design synthetic antigenic peptides. Virus-like particles are being designed for vaccine deliveries that are based on structures of viral capsid proteins and other synthetic lipopeptide building blocks. A new generation of adjuvants is being developed to further enhance immunogenicity, based on squalene and other oil-water emulsions, saponins, muramyl dipeptide, immunostimulatory oligonucleotides, Toll-like receptor ligands, and lymphotoxins. Finally, current trends in engineering of therapeutic antibodies including improvements of antigen-binding properties, pharmacokinetic and pharmaceutical properties, and reduction of immunogenicity are discussed. Taken together, understanding the chemistry of vaccine design, delivery and immunostimulation, and knowledge of the techniques of antibody design are allowing targeted development for the treatment of chronic disorders characterized by continuing activation of the immune system, such as autoimmune disorders, cancer, or allergies that have long been refractory to conventional approaches.

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High-avidity human IgGκ monoclonal antibodies from a novel strain of minilocus transgenic mice

Cited by 253 publications

References 49 publications

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

High Turnover of Tissue Factor Enables Efficient Intracellular Delivery of Antibody–Drug Conjugates

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

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