Humanization of an anti-p185HER2 antibody for human cancer therapy.

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dc.creatorCarter, P
dc.creatorPresta, L
dc.creatorGorman, C M
dc.creatorRidgway, J B
dc.creatorHenner, D
dc.creatorWong, W L
dc.creatorRowland, A M
dc.creatorKotts, C
dc.creatorCarver, M E
dc.creatorShepard, H M
dc.date1992-05-15
dc.date.accessioned2026-08-03T01:33:10Z
dc.descriptionThe murine monoclonal antibody mumAb4D5, directed against human epidermal growth factor receptor 2 (p185HER2), specifically inhibits proliferation of human tumor cells overexpressing p185HER2. However, the efficacy of mumAb4D5 in human cancer therapy is likely to be limited by a human anti-mouse antibody response and lack of effector functions. A "humanized" antibody, humAb4D5-1, containing only the antigen binding loops from mumAb4D5 and human variable region framework residues plus IgG1 constant domains was constructed. Light- and heavy-chain variable regions were simultaneously humanized in one step by "gene conversion mutagenesis" using 311-mer and 361-mer preassembled oligonucleotides, respectively. The humAb4D5-1 variant does not block the proliferation of human breast carcinoma SK-BR-3 cells, which overexpress p185HER2, despite tight antigen binding (Kd = 25 nM). One of seven additional humanized variants designed by molecular modeling (humAb4D5-8) binds the p185HER2 antigen 250-fold and 3-fold more tightly than humAb4D5-1 and mumAb4D5, respectively. In addition, humAb4D5-8 has potency comparable to the murine antibody in blocking SK-BR-3 cell proliferation. Furthermore, humAb4D5-8 is much more efficient in supporting antibody-dependent cellular cytotoxicity against SK-BR-3 cells than mumAb4D5, but it does not efficiently kill WI-38 cells, which express p185HER2 at lower levels. IMAGES:
dc.identifierhttps://pmc.ncbi.nlm.nih.gov/articles/PMC49066/
dc.identifierhttps://pubmed.ncbi.nlm.nih.gov/1350088/
dc.identifierhttps://doi.org/10.1073/pnas.89.10.4285
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/155715
dc.languageen
dc.publisherNational Academy of Sciences
dc.sourceProc Natl Acad Sci U S A
dc.subjectResearch Article
dc.titleHumanization of an anti-p185HER2 antibody for human cancer therapy.
dc.typeText

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