Preclinical Therapy of Breast Cancer with a Radioiodinated Humanized Anti-EGP-1 Monoclonal Antibody: Advantage of a Residualizing Iodine Radiolabel

Govindan, Serengulam V.; Stein, Rhona; Qu, Zhengxing; Chen, Susan; Andrews, Philip M.; Ma, Hong; Hansen, Hans J.; Griffiths, Gary L.; Horak, Ivan D.; Goldenberg, David M.

doi:10.1023/b:brea.0000018417.02580.ef

Cited by 48 publications

(42 citation statements)

References 14 publications

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“…25 In addition, a humanized version of RS7 (hRS7) was generated with promising results in an in vivo breast cancer model. 26 Taken together, our data support the assumption that TROP2 plays an important role in tumor growth. However, due to the limitations inherent in retrospective analyses, the prognostic value of TROP2 overexpression needs to be validated in larger prospective studies.…”

Section: Discussionsupporting

confidence: 84%

TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity

et al. 2008

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Squamous cell carcinoma is by far the most common type of cancer of the oral cavity, representing more than 90% of all oral cancers. Despite refinement of surgical techniques and adjuvant therapies, the prognosis for patients with oral squamous cell carcinoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment. Recently, the human trophoblast cell-surface antigen TROP2 was found to be highly expressed in colorectal cancer, correlating with aggressiveness and poor prognosis. Thus, the aim of this study was to investigate TROP2 expression and its prognostic impact in oral squamous cell carcinoma patients. TROP2 expression was examined by immunohistochemistry in a series of 90 patients on a tissue microarray of paraffin-embedded specimens. Survival was calculated using Kaplan-Meier estimates. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 52 (58%) of the tumor samples. Kaplan-Meier curves showed that TROP2 overexpression was significantly associated with decreased overall survival (Po0.01). Overall survival gradually worsened with increasing TROP2 scores. By univariate analyses, no correlation with conventional clinicopathological features was found. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent factor predictive of poor disease outcome (Po0.01). These results demonstrate that TROP2 overexpression is an independent prognostic marker in patients with oral squamous cell carcinoma. TROP2 overexpression was detectable in 58% of the tumor samples, indicating it to be a potential novel therapeutic target in squamous cell carcinoma of the oral cavity.

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Section: Discussionsupporting

confidence: 84%

TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity

et al. 2008

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“…Indeed, radiolabelled RS7 has been applied for tumour imaging and revealed significant antitumour activity in several animal models (Shih et al, 1995;Stein et al, 1999c). Meanwhile, RS7 was successfully humanised and showed promising antitumour effects in an in vivo breast cancer model (Govindan et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

High expression of TROP2 correlates with poor prognosis in pancreatic cancer

et al. 2008

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Pancreatic cancer is one of the most devastating human malignancies. Despite considerable research efforts, it remains resistant to almost all available treatment regimens. The human trophoblast cell-surface antigen, TROP2, was found to be strongly expressed in a variety of human epithelial cancers, correlating with aggressiveness and poor prognosis. TROP2 antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series (n ¼ 197) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated using Kaplan -Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 109 (55%) of 197 pancreatic cancer patients and was significantly associated with decreased overall survival (Po0.01). By univariate analysis, TROP2 overexpression was found to correlate with the presence of lymph node metastasis (P ¼ 0.04) and tumour grade (P ¼ 0.01). Furthermore, in the subgroup of patients treated surgically with curative intent, TROP2 overexpression significantly correlated with poor progression-free survival (Po0.01). Multivariate analyses revealed TROP2 to be an independent prognosticator. These findings suggest for the first time that TROP2 could be a novel prognostic biomarker for pancreatic cancer. Targeting TROP2 might be a useful treatment approach for patients with pancreatic cancer overexpressing this cell-surface marker.

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“…This mAb has been characterized previously and has been shown to be reactive with an extracellular domain of CD74 (5). LL1 mAb has been humanized according to an approach used for three other mAbs (13)(14)(15). It has been shown to retain the binding characteristics of the original murine mAb (16).…”

Section: Methodsmentioning

confidence: 99%

CD74 Is Expressed by Multiple Myeloma and Is a Promising Target for Therapy

Burton

Ely

Reddy

et al. 2004

Clinical Cancer Research

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143

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Purpose: CD74 (HLA-DR-associated invariant chain) plays a role in antigen presentation. In addition to its expression on antigen-presenting cells, it is expressed by carcinomas of renal, lung, gastric, and thymic origin and by certain sarcomas. The restricted expression of CD74 by normal tissues and its very rapid internalization make CD74 an attractive therapeutic target for both cancer and immunologic diseases. Preclinical efficacy of anti-CD74 monoclonal antibody (mAb) therapy has been demonstrated in B-lymphoma models. Because there are few validated antigenic targets in multiple myeloma, CD74 expression was examined.Experimental Design: CD74 expression was assessed by immunohistochemistry in bone marrow biopsies of known multiple myeloma cases. Its expression was measured by flow cytometry in multiple myeloma lines, and CD74 mRNA expression was determined by reverse transcription-PCR. In addition, the in vitro antiproliferative effect of LL1 mAb was evaluated on a CD74؉ multiple myeloma cell line using a [ 3 H]thymidine incorporation assay.Results: CD74 expression was observed in 19 of 22 cases of multiple myeloma, with most expressing moderate to high levels in the majority of malignant plasma cells. CD74 was expressed by most multiple myeloma cell lines, as was CD74 mRNA, at levels mirroring CD74 protein. Also, unlabeled LL1 mAb mediated in vitro growth inhibition of a CD74؉ multiple myeloma cell line.Conclusions: CD74 expression is frequent in multiple myeloma, with predominant expression by the malignant plasma cells. Because anti-CD74 mAbs internalize very rapidly and LL1 mAb has shown efficacy in B-lymphoma models, CD74 represents a novel and promising target for treatment of multiple myeloma. Therefore, LL1 mAb is well suited as a carrier of radionuclides, drugs, or toxins, and also has activity as an unlabeled mAb, thereby supporting its development for this unmet need in cancer therapy.

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Preclinical Therapy of Breast Cancer with a Radioiodinated Humanized Anti-EGP-1 Monoclonal Antibody: Advantage of a Residualizing Iodine Radiolabel

Abstract: 131I-IMP-R4-hRS7 is a promising new agent for RAIT, providing significant therapeutic advantage in comparison to the conventionally 131I-labeled antibody.

Cited by 48 publications

References 14 publications

TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity

TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity

High expression of TROP2 correlates with poor prognosis in pancreatic cancer

CD74 Is Expressed by Multiple Myeloma and Is a Promising Target for Therapy

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