{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T03:17:37Z","timestamp":1788405457367,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,7,18]],"date-time":"2006-07-18T00:00:00Z","timestamp":1153180800000},"content-version":"vor","delay-in-days":4008,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[1995,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We previously constructed a humanized anti\u2010p185<jats:sup>HER2<\/jats:sup>\/anti\u2010CD3 bispecific antibody variant, BsF(ab\u2032)<jats:sub>2<\/jats:sub> v1 which retargets the cytotoxic activity of human T cells in vitro against human breast tumor cells which overexpress the p185<jats:sup>HER2<\/jats:sup> product of the <jats:italic>HER2\/neu<\/jats:italic> (c\u2010<jats:italic>erb<\/jats:italic>B\u20102) protooncogene. Subsequently we identified an improved anti\u2010CD3 variant, v9, which binds to T cells with approx. 100\u2010fold higher affinity than the original variant, v1. Here we demonstrate that BsF(ab\u2032)<jats:sub>2<\/jats:sub> v9 is more potent than BsF(ab\u2032)<jats:sub>2<\/jats:sub> v1 in stimulating the proliferation of both resting peripheral blood lymphocytes (PBL) and IL\u20102\u2010activated, long\u2010term cultured T lymphocytes (ATL). In addition, at low concentrations (0.01\u20101 ng\/ml) BsF(ab\u2032)<jats:sub>2<\/jats:sub> v9 is much more efficient than BsF(ab)<jats:sub>2<\/jats:sub> v1 in directing lysis of p185<jats:sup>HER2<\/jats:sup>\u2010overexpressing tumor cells by IL\u20102 activated PBL. In contrast, at higher concentration BsF(ab\u2032)<jats:sub>2<\/jats:sub> v9 and BsF(ab\u2032)<jats:sub>2<\/jats:sub> v1 have similar potency in retargeted cytotoxicity. At BsF(ab\u2032)<jats:sub>2<\/jats:sub> v9 concentrations of \u2a7e 1 ng\/ml the susceptibility of p185<jats:sup>HER2<\/jats:sup>\u2010expressing tumor cells to lysis is apparently independent of the level of p185<jats:sup>HER2<\/jats:sup> expression. At lower concentrations of BsF(ab\u2032)<jats:sub>2<\/jats:sub> v9 and\/or lower ratios of effector to target cells the extent of lysis is reduced, in some cases improving the selectivity of lysis of high p185<jats:sup>HER2<\/jats:sup> expressors over low expressors. Thus selection of a high affinity anti\u2010CD3 arm is likely important in the design of BsF(ab\u2032)<jats:sub>2<\/jats:sub> for retargeting the cytotoxicity of T cells to tumors. The dose of BsF(ab\u2032)<jats:sub>2<\/jats:sub> v9 in any future clinical evaluation will require optimization to maximize anti\u2010tumor efficacy whilst minimizing potential toxicity against normal tissue expressing p185<jats:sup>HER2<\/jats:sup>. \u00a9 1995 Wiley\u2010Liss Inc.<\/jats:p>","DOI":"10.1002\/ijc.2910620315","type":"journal-article","created":{"date-parts":[[2007,2,20]],"date-time":"2007-02-20T00:47:36Z","timestamp":1171932456000},"page":"319-324","source":"Crossref","is-referenced-by-count":39,"title":["Engineering high affinity humanized anti\u2010p185<sup>HER2<\/sup>\/anti\u2010CD3 bispecific F(ab\u2032)2 for efficient lysis of p185<sup>HER2<\/sup> overexpressing tumor cells"],"prefix":"10.1002","volume":"62","author":[{"given":"Zhenping","family":"Zhu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail D.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,7,18]]},"reference":[{"key":"e_1_2_1_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830110412"},{"key":"e_1_2_1_2_1","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1182\/blood.V82.6.1803.1803","article-title":"Lysis of malignant B cells from patients with B\u2010chronic lymphocytic leukemia by autologous T cells activated with CD3 x CD19 bispecific antibodies in combination with bivalent CD28 antibodies","volume":"82","author":"Bohlen H.","year":"1993","journal-title":"Blood"},{"key":"e_1_2_1_3_1","unstructured":"Bolhuis R. L. Lamers C. H. J. Goey S. H. Eggermont A. M. M. Trimbos J. B. M. Z. Stoter G. Lanzavecchia A. di Re E. Miotti S. Raspagliesi F. Rivoltini L.andColnighi M. I. Adoptive immunotherapy of ovarian carcinoma with bs\u2010mAb\u2010targeted lymphocytes: a multicenter study.Int. J. Cancer(Suppl. 7) 78\u201381(1992)."},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0292-163"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.10.4285"},{"key":"e_1_2_1_6_1","volume-title":"Antibody engineering: a practical approach","author":"Carter P.","year":"1995"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.340180107"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(91)90156-N"},{"key":"e_1_2_1_9_1","first-page":"1550","article-title":"Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2\/ neu gene product","volume":"50","author":"Fendly B. M.","year":"1989","journal-title":"Cancer Res."},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910550610"},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00002371-199410000-00004"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910600405"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01518520"},{"key":"e_1_2_1_14_1","first-page":"74","article-title":"Cell surface receptors and bispecific monoclonal antibodies: the link between science and medical oncology","volume":"7","author":"Malavasi F.","year":"1993","journal-title":"Year Immunol."},{"key":"e_1_2_1_15_1","first-page":"163","article-title":"Targeted cellular immunotherapy with bifunctional antibodies","volume":"3","author":"Nelson H.","year":"1991","journal-title":"Cancer Cells"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910500523"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(90)90205-J"},{"key":"e_1_2_1_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-3500-3_10"},{"key":"e_1_2_1_19_1","first-page":"433","article-title":"Targeting of HER\u20102\/ neu overexpressing breast and ovarian cancers with humanized bispecific F(ab)2 ap185HER2\/\u03b1CD3 and human LAK cellsin vivo","volume":"36","author":"Pegram M.","year":"1995","journal-title":"Proc. Amer. Assoc. Cancer Res."},{"key":"e_1_2_1_20_1","first-page":"953","article-title":"Expression of the HER\u20102\/neu proto\u2010oncogene in normal human adult and fetal tissues","volume":"5","author":"Press M. F.","year":"1990","journal-title":"Oncogene"},{"key":"e_1_2_1_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8171337"},{"key":"e_1_2_1_22_1","unstructured":"Rodrigues M. L. Shalaby M. R. Werther W. Presta L.andCarter P. Engineering a humanized bispecific F(ab')2fragment for improved binding to T cells.Int. J. Cancer(Suppl. 7)45\u201350(1992)."},{"key":"e_1_2_1_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.170.1.297"},{"key":"e_1_2_1_24_1","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1995.1027"},{"key":"e_1_2_1_25_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.1.217"},{"key":"e_1_2_1_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3798106"},{"key":"e_1_2_1_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2470152"},{"key":"e_1_2_1_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.1992.tb00126.x"},{"key":"e_1_2_1_29_1","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.4049\/jimmunol.152.5.2385","article-title":"The role of T cell activation in anti\u2010CD3 antitumor bispecific antibody therapy","volume":"152","author":"Weiner G. J.","year":"1994","journal-title":"J. Immunol."}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fijc.2910620315","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.2910620315","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T05:44:19Z","timestamp":1698299059000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.2910620315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,7,28]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[1995,7,28]]}},"alternative-id":["10.1002\/ijc.2910620315"],"URL":"https:\/\/doi.org\/10.1002\/ijc.2910620315","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,7,28]]}}}