Phase I Trial of the Anti–Lewis Y Drug Immunoconjugate BR96-Doxorubicin in Patients With Lewis Y–Expressing Epithelial Tumors

Saleh, Mansoor N.; Sugarman, Steve; Murray, James H.; Ostroff, Joy B.; Healey, Diane; Jones, D. D.; Daniel, Carol R.; LeBherz, Donna; Brewer, Hannah; Onetto, Nicole; LoBuglio, Albert F.

doi:10.1200/jco.2000.18.11.2282

Cited by 160 publications

(100 citation statements)

References 10 publications

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“…The binding specificity of Sfrs provides a rationale for why tumor cells expressing LeY antigen, LeB antigen, or type 1H antigen often metastasize to the lung (6,11,32). LeY antigen is considered a primary target of cancer therapy using humanized monoclonal antibodies (33)(34)(35) and by cancer vaccine with LeY mimicry peptide (36, 37). Our study supports strategies targeting LeY antigen in breast, lung, ovary, and colon cancers (6,38,39).…”

Section: Discussionmentioning

confidence: 99%

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Hatakeyama

Sato

Nakayama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cell surfaces of epithelial cancer are covered by complex carbohydrates, whose structures function in malignancy and metastasis. However, the mechanism underlying carbohydrate-dependent cancer metastasis has not been defined. Previously, we identified a carbohydrate-mimicry peptide designated I-peptide, which inhibits carbohydrate-dependent lung colonization of sialyl Lewis X-expressing B16-FTIII-M cells in E/P-selectin doubly-deficient mice. We hypothesized that lung endothelial cells express an unknown carbohydrate receptor, designated as I-peptide receptor (IPR), responsible for lung colonization of B16-FTIII-M cells. Here, we visualized IPR by in vivo biotinylation, which revealed that the major IPR is a group of 35-kDa proteins. IPR proteins isolated by I-peptide affinity chromatography were identified by proteomics as Ser/Arg-rich alternative pre-mRNA splicing factors or Sfrs1, Sfrs2, Sfrs5, and Sfrs7 gene products. annexin ͉ galectin ͉ metastasis ͉ selectin ͉ vasculature T he apical cell surface of epithelia is covered by numerous carbohydrates attached to membrane proteins and lipids. When epithelial cells are transformed, the structure of these carbohydrates changes (1). Many investigators have suggested a correlation between cancer-associated carbohydrate antigens and poor patient prognosis, including metastasis (2-8). Despite extensive structural analysis and clinical observations using monoclonal antibodies against cancer-associated carbohydrate antigens, mechanisms underlying carbohydrate-dependent cancer metastasis through the circulation remain elusive. Because E-selectin is expressed on the inflammatory endothelial cell surface and binds to cancer-associated carbohydrate antigens such as sialyl Lewis A (sLeA) and sialyl Lewis X (sLeX), E-selectin provides a mechanism for sLeA and/or sLeX antigenexpressing cancer cells to be metastasized through the hematogenous route (4-6). Involvement of P-selectin and L-selectin in cancer metastasis has been also described (7,8). However, substantial clinical data indicate the existence of selectin-independent but carbohydrate-dependent cancer metastasis (6, 10, 11).In our previous studies, we screened a peptide-displaying phage library using a monoclonal anti-Lewis A antibody (clone 7LE) and identified a short peptide IELLQAR, designated I-peptide (12-14). When I-peptide was injected intravenously into a mouse, it bound to a specific subset of lung capillary endothelial cells but not to blood vessels of other organs including the liver (12). I-peptide administration inhibited carbohydrate-dependent lung colonization of fucosyltransferase-3-transfected sialyl Lewis X antigenpositive B16 (B16-FTIII-M) cells (15) in wild-type mice (12) and in E-and P-selectin doubly-deficient mutant mice (13), suggesting that the lung endothelial surface expresses unknown carbohydratebinding receptor(s) enabling colonization of B16-FTIII-M cells. We designated this presumptive receptor I-peptide receptor (IPR) (13).In this study, we isolated IPR candidate proteins by I-peptideaff...

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Section: Discussionmentioning

confidence: 99%

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Hatakeyama

Sato

Nakayama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In phase I and II clinical trials of this conjugate, patients with metastatic breast cancer experienced a marked decrease in side effects, in comparison with unconjugated doxorubicin administration. However, unconjugated doxorubicin showed increased potent antitumor activity (Tolcher et al, 1999;Saleh et al, 2000).…”

Section: Immunotoxinsmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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“…The safety of this approach is supported by the favorable toxicity profile of various 'naked' and conjugated anti-Le Y antibodies in early phase clinical studies, as well as the lack of transforming events in T cells retrovirally transduced to express this construct. [37][38][39][40] An alternative to the use of chimeric T cells for the treatment of Le Y expressing malignancies is the less cumbersome utilization of monoclonal antibodies. [38][39][40] However, chimeric T cells as used in this study effectively combine antigen specificity with direct activation of the most potent immune effector cells upon antigen binding.…”

Section: Discussionmentioning

confidence: 99%

“…[37][38][39][40] An alternative to the use of chimeric T cells for the treatment of Le Y expressing malignancies is the less cumbersome utilization of monoclonal antibodies. [38][39][40] However, chimeric T cells as used in this study effectively combine antigen specificity with direct activation of the most potent immune effector cells upon antigen binding. Therefore, in our opinion, chimeric T cells are more likely to mount …”

Section: Discussionmentioning

confidence: 99%

Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen

et al. 2010

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Phase I Trial of the Anti–Lewis Y Drug Immunoconjugate BR96-Doxorubicin in Patients With Lewis Y–Expressing Epithelial Tumors

Cited by 160 publications

References 10 publications

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Novel antibodies as anticancer agents

Gene-modified T cells as immunotherapy for multiple myeloma and acute myeloid leukemia expressing the Lewis Y antigen

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