Replacing the complementarity-determining regions in a human antibody with those from a mouse

Jones, Peter; Dear, Paul H.; Foote, Jefferson; Neuberger, Michael S.; Winter, Greg

doi:10.1038/321522a0

Cited by 1,241 publications

(555 citation statements)

References 27 publications

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“…The CDRs of the murine antibody were grafted on to the FRs of two different human IgGs, the B43 heavy chain, and the REI light chain, without molecular modeling (Jones et al, 1986). No changes in the human FR amino acids of the light chain were made.…”

Section: Discussionmentioning

confidence: 99%

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Boado

Zhang

et al. 2006

Biotech & Bioengineering

177

138

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A murine monoclonal antibody (MAb) to the human insulin receptor (HIR) has been engineered for use as a brain drug delivery system for transport across the human blood-brain barrier (BBB). The HIRMAb was humanized by complementarity determining region (CDR) grafting on the framework regions (FR) of the human B43 IgG heavy chain and the human REI kappa light chain. A problem encountered in the humanization process was the poor secretion of the CDR-grafted HIRMAb by myeloma cells. This problem was solved by the production of human/mouse hybrids of the engineered heavy chain variable region (VH), which led to the replacement of five amino acids in the FR3 of the VH with original murine amino acids. No replacement of FR amino acids in the light chain variable region (VL) was required. The affinity of the humanized HIRMAb for the HIR was decreased 27% relative to the murine HIRMAb. The humanized HIRMAb avidly bound to the HIR of isolated human brain capillaries, which are used as an in vitro model system of the human BBB. The HIRMAb cross reacts with the HIR of Old World primates such as the Rhesus monkey. The humanized HIRMAb was radiolabeled with 125-iodine, and injected intravenously into an adult, anesthetized Rhesus monkey. Brain scanning showed the humanized HIRMAb was rapidly transported into all parts of the primate brain after intravenous administration. The humanized HIRMAb may be used as a brain drug and gene delivery system for the targeting of large molecule therapeutics across the BBB in humans.

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Section: Discussionmentioning

confidence: 99%

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Boado

Zhang

et al. 2006

Biotech & Bioengineering

177

138

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“…Preparation of humanised hHMFG1 monoclonal antibody Verhoeyen et al (1993) developed the anti-Polymorphic Epithelial Mucin, PEM, humanised monoclonal antibody (human milk fat globule 1), hHMFG1 by genetic engineering (Jones et al, 1986;Riechmann et al, 1988;Gorman et al, 1991). The master cell culture was shown to be virus free when used for the production of hHMFG1.…”

Section: Methodsmentioning

confidence: 99%

Axillary node status in breast cancer patients prior to surgery by imaging with Tc-99m humanised anti-PEM monoclonal antibody, hHMFG1

et al. 2002

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In early breast cancer axillary nodes are usually impalpable and over 50% of such patients may have an axillary clearance when no nodes are involved. This work identifies axillary node status by imaging with a Tc-99m radiolabelled anti-Polymorphic Epithelial Mucin, humanised monoclonal antibody (human milk fat globule 1), prior to surgery in 30 patients. Change detection analysis of image data with probability mapping is undertaken. A specificity of 93% and positive predictive value of 92% (both 100% if a second cancer in the axilla with negative nodes is considered) were found. A strategy for combining negative imaging with the sentinel node procedure is presented.

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“…Certolizumab pegol differs from infliximab and adalimumab in that it is composed of a humanized TNFa specific Fab conjugated to polyethylene glycol [57]. Humanized antibodies are created by replacing human complementarity-determining regions with mouse-derived components, while maintaining the remainder of the human antibody [58]. Humanization in theory may lead to a lower frequency of developing antidrug antibodies [59].…”

Section: Currently Available Therapeutic Antibodies In Digestive Disementioning

confidence: 99%

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

Sofia

Rubin

2017

Dig Dis Sci

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The development of therapeutic antibodies represents a revolutionary change in medical therapy for digestive diseases. Beginning with the initial studies that confirmed the pathogenicity of cytokines in inflammatory bowel disease, the development and application of therapeutic antibodies brought challenges and insights into their potential and optimal use. Infliximab was the first biological drug approved for use in Crohn's disease and ulcerative colitis. The lessons learned from infliximab include the importance of immunogenicity and the influence of pharmacokinetics on disease response and outcomes. Building on this foundation, other therapeutic antibodies achieved approval for inflammatory bowel disease and many more are in development for several digestive diseases. In this review, we reflect on the history of therapeutic antibodies and discuss current practice and future directions for the field.

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Replacing the complementarity-determining regions in a human antibody with those from a mouse

Cited by 1,241 publications

References 27 publications

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Humanization of anti‐human insulin receptor antibody for drug targeting across the human blood–brain barrier

Axillary node status in breast cancer patients prior to surgery by imaging with Tc-99m humanised anti-PEM monoclonal antibody, hHMFG1

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

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