Production of functional chimaeric mouse/human antibody

Abstract

The availability of monoclonal antibodies has revived interest in immunotherapy. The ability to influence an individual's immune state by administering immunoglobulin of the appropriate specificity may provide a powerful approach to disease control and prevention. Compared with immunoglobulin from other species, human immunoglobulin (Ig) might be best for such therapeutic intervention; it might function better with the recipient's effector cells and should itself be less immunogenic. The success of the mouse hybridoma system suggests that immunoglobulin of virtually any specificity can be obtained from a properly immunized animal. In the human system, however, immunization protocols are restricted by ethical considerations, and it is not yet clear whether human antibody-producing cell lines of the required specificity can be obtained from adventitiously immunized individuals or from in vitro immunized cells. A method which might circumvent these difficulties is to produce antibodies consisting of mouse variable regions joined to human constant regions. Therefore, we have constructed immunoglobulin genes in which the DNA segments encoding mouse variable regions specific for the hapten trinitrophenyl (TNP) are joined to segments encoding human mu and kappa constant regions. These 'chimaeric' genes are expressed as functional TNP-binding chimaeric IgM. We report here some of the properties of this novel IgM.

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions

“…Even at this early stage in development, the science revealed the challenge of maintaining tolerance to such therapeutic antibodies. Chimeric antibodies were developed to meet this challenge by fusing mouse variable domain regions to human constant regions [7]. By the early 1990s, the stage was set with the emerging understanding of TNFa in inflammatory diseases and the technology to target this protein with chimeric antibodies.…”

Convenient plasmid vectors for construction of chimeric mouse/human antibodies

“…Variable (V) regions bind antigens (Ag) and constant (C) parts bear effector functions Correspondence address: Y. Kurosawa, Institute for Comprehensive Medical Science, Fujita-Gakuen Health University, Toyoake, Aichi 470-l 1, Japan Abbreviations: Ab, antibody; Ag, antigen; C, constant; D, diversity; ELISA, enzyme-linked immunosorbent assay; H, heavy; Ig, immunoglobulin; J, joining; L, light; PAB, pazobenzenarsonate; PAGE, polyacrylamide gel electrophoresis; PBS, phosphate-buffered saline; PC, phosphorylcholine; V, variable such as binding and activation of complements, stimulation of phagocytosis by macrophages, and triggering of granule release by mast cells. Utilizing the dual characters in the structure of Ab, two research groups [3,4] succeeded in constructing chimeric molecules consisting of mouse-derived V regions and human-derived C regions. These chimeric Ab retained specificity for the haptens phosphorylcholine (PC) [3] and trinitrophenyl [4].…”

“…Utilizing the dual characters in the structure of Ab, two research groups [3,4] succeeded in constructing chimeric molecules consisting of mouse-derived V regions and human-derived C regions. These chimeric Ab retained specificity for the haptens phosphorylcholine (PC) [3] and trinitrophenyl [4]. Since these studies several groups have reported production of similar chimeric Ab showing antitumor activities [5-l 11.…”

Effects of neocarzinostatin-chimeric Fab conjugates on the growth of human pancreatic carcinoma xenografts

“…However, human anti-mouse antibody (HAMA) was detected in all of the patients who received A7-NCS (Spiegelberg and Weigle, 1965). The latest approach has been the production of human/mouse chimeric antibodies composed of the antigen-binding variable region from a murine MAb and the constant region of a human immunoglobulin (Morrison et al, 1984;Boulianne et al, 1984). Since the constant region of the mouse/human chimeric antibody is human, HAMA production should be decreased.…”