Construction and initial characterization of a mouse-human chimeric anti-TNF antibody

doi:10.1016/0161-5890(93)90106-L

Molecular Immunology

Volume 30, Issue 16, November 1993, Pages 1443-1453

https://doi.org/10.1016/0161-5890(93)90106-L Get rights and content

Abstract

Tumor necrosis factor-α (TNF) has been implicated in the pathogenesis of a variety of human diseases including septic shock, cachexia, graft-versus-host disease and several autoimmune diseases. Monoclonal antibodies directed against TNF provide an attractive mode of therapeutic intervention in these diseases. We have generated a murine monoclonal antibody (A2) with high affinity and specificity for recombinant and natural human TNF. To increase its therapeutic usefulness, we used genetic engineering techniques to replace the murine constant regions with human counterparts while retaining the murine antigen binding regions. The resulting mouse—human chimeric antibody should have reduced immunogenicity and improved pharmacokinetics in humans. Molecular analysis of light chain genomic clones derived from the murine hybridoma suggests that two different alleles of the same variable region gene have rearranged independently and coexist in the same hybridoma cell. The chimeric A2 antibody (cA2) exhibits better binding and neutralizing characteristics than the murine A2 which was shown to contain a mixture of two kappa light chains. The properties of cA2 suggest that it will have advantages over existing murine anti-TNF antibodies for clinical use.

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Construction and initial characterization of a mouse-human chimeric anti-TNF antibody

Abstract

J. Autoimmun.

The Lancet

Molec. Immunol.

Lancet

J. molec. Biol.

Curr. Opin. Immunol.

IL-6 inhibits lipopolysaccharide-induced tumor necrosis factor production in cultured human monocytes, U937 cells and in mice

J. Immunol.

Tumor necrosis, cachexia, shock and inflammation: a common mediator

A. Rev. Biochem.

Production of functional chimeric mouse/human antibody

Nature

Cytokine expression in rheumatoid arthritis

Br. J. Rheumatol.

Increased levels of soluble tumor necrosis factor receptors in the sera and synovial fluid of patients with rheumatic diseases

Arth. Rheum.

Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis

Arth. Rheum.

Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to TNFα: safety, clinical efficacy and control of the acute-phase response

J. cell. Biochem.

The role of somatic hypermutation in the generation of antibody diversity

Science

Tumor necrosis factor alpha mediates lethal activity of killed gram-negative and gram-positive bacteria in D-Galactosamine-treated mice

Infect. Immun.

Characterization of a human T cell-specific chimeric antibody (CD7) with human constant and mouse variable regions

J. Immunol.

Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNFα)

Circ. Shock

Tumor necrosis factor identified in multiple sclerosis brain

J. exp. Med.

Tumor necrosis factor α in murine autoimmune lupus nephritis

Nature

Survival of primates in LD₁₀₀ septic shock following therapy with antibody to tumor necrosis factor (TNFα)