Advantage of a Residualizing Iodine Radiolabel in the Therapy of a Colon Cancer Xenograft Targeted with an Anticarcinoembryonic Antigen Monoclonal Antibody

Stein, Rhona; Govindan, Serengulam V.; Hayes, Marianne K.; Griffiths, Gary L.; Hansen, Hans J.; Horak, Ivan D.; Goldenberg, David M.

doi:10.1158/1078-0432.ccr-04-2100

Cited by 19 publications

(17 citation statements)

References 36 publications

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“…CEACAM5 is traditionally considered non-internalizing, but a number of reports show that slow internalization of CEACAM5 and, with it, the targeted antibody, occurs due to membrane turnover (33−35). Internalization and intracellular processing of labetuzumab on two colonic cancer cell lines in vitro also has been described (36). …”

Section: Discussionmentioning

confidence: 99%

CEACAM5-Targeted Therapy of Human Colonic and Pancreatic Cancer Xenografts with Potent Labetuzumab-SN-38 Immunoconjugates

Govindan

Cardillo

Moon

et al. 2009

Clinical Cancer Research

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Purpose: To improve the efficacy and reduce the gastrointestinal toxicity of the cancer prodrug, CPT-11, we have developed immunoconjugates of its active form, SN-38, and an anti-CEACAM5 antibody for targeted chemotherapy. Experimental Design: SN-38 conjugates of the anti-CEACAM5 monoclonal antibody, labetuzumab , varying in the nature of the cross-linker attachment at the drug's 20-hydroxyl position, were evaluated in vitro, in metastatic and/or s.c. human colonic and pancreatic cancer xenografts in nude mice using appropriate controls, and in a CEACAM5-negative tumor model. Results: A pilot study in a s.c. LS174T model of human colonic carcinoma established the relative effectiveness of different conjugates. In the lung metastatic model of GW-39 human colonic carcinoma in nude mice, therapy with two specific labetuzumab-SN-38 conjugates, using 0.25 mg SN-38 equivalent/kg, q4d × 8, significantly extended median survival time versus controls (P < 0.002). In an expanded evaluation in the s.c. LS174T xenograft model, specific SN-38 conjugates produced significant tumor growth control and increases in median survival time versus other controls, including CPT-11 at a 33-fold greater cumulative dose (P < 0.01). An improvement was also observed in the therapy of a s.c. human pancreatic tumor xenograft. In a CEACAM5-negative systemic lymphoma xenograft, one labetuzumab-SN-38 conjugate examined was ineffective, whereas the conjugate specific for the tumor model produced 100% survival. Conclusions: The promising labetuzumab-SN-38 conjugates developed showed selective therapeutic efficacy in human tumor models at nontoxic doses that were a fraction of the CPT-11 doses used. (Clin Cancer Res 2009;15(19):6052-61) CPT-11 (irinotecan) is a water-soluble prodrug in clinical use for the treatment of metastatic colorectal cancer, and is also clinically active in lung, cervical, and ovarian cancers (1, 2). It is additionally used in combination therapies with other cancer drugs and biological agents. CPT-11 is converted by human carboxylesterase in vivo to its active form, SN-38, which is more potent by two to three orders of magnitude (3). Both CPT-11 and SN-38 belong to the camptothecin (CPT) group of antitumor compounds that inhibit topoisomerase I by stabilizing the DNA-topo I complex (4-6). Structures are shown in Fig. 1.The in vivo conversion to the active drug is not efficient (7). Furthermore, SN-38 is converted to its glucuronide, SN-38G, in a detoxification mechanism, and is reconverted back to the active drug by intestinal glucuronidase, thereby causing severe delayed diarrhea (8). In addition, CPT-11 and SN-38 undergo lactone (E-ring)-opening in vivo, with the open carboxylate form further stabilized by complexation with human serum albumin. Because the carboxylate form has only 10% of the drug activity as the intact lactone form, this in vivo lactone opening diminishes drug potency (9, 10). CPT-11 also undergoes oxidative transformations mediated by cytochrome P450, and the metabolites are poorer substrat...

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Section: Discussionmentioning

confidence: 99%

CEACAM5-Targeted Therapy of Human Colonic and Pancreatic Cancer Xenografts with Potent Labetuzumab-SN-38 Immunoconjugates

Govindan

Cardillo

Moon

et al. 2009

Clinical Cancer Research

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“…Any anti-tumor mAb that is capable of activating complement could be used in combination with β-glucan for tumor therapy. In addition to current FDA-approved anti-tumor Abs, there are also more and more anti-tumor mAbs that have been developed or are being developed to treat cancer, such as anti-CEA Ab in colorectal cancer (Stein et al, 2005) and anti-carbonic anhydrase IX Ab in clear cell renal cell carcinoma (Davis et al, 2007). Increases in the number of anti-tumor Abs offer more opportunities to design versatile combinations with β-glucan therapy.…”

Section: Current and Future Challengesmentioning

confidence: 99%

Combined yeast-derived β-glucan with anti-tumor monoclonal antibody for cancer immunotherapy

Liu

Gunn

Hansen

et al. 2009

Experimental and Molecular Pathology

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β-Glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAbs therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (Erbitux) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients.

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“…This led to the development of reagents such as N-succinimidyl 3-[*I]iodobenzoate (SIB), which yield proteins that do not undergo appreciable deiodination in vivo based on their Tyr-dissimilar structure 1,2 . However, when a labeled protein or peptide undergoes cellular internalization after binding to a cell surface receptor or antigen, then, depending on its intercellular routing, considerable loss of label from the targeted cell can occur [3][4][5] . Although this discussion is focused on mAbs for simplicity of presentation, this problem can affect other proteins and peptides also.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides

Vaidyanathan

Zalutsky

2007

Nat Protoc

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Advantage of a Residualizing Iodine Radiolabel in the Therapy of a Colon Cancer Xenograft Targeted with an Anticarcinoembryonic Antigen Monoclonal Antibody

Cited by 19 publications

References 36 publications

CEACAM5-Targeted Therapy of Human Colonic and Pancreatic Cancer Xenografts with Potent Labetuzumab-SN-38 Immunoconjugates

CEACAM5-Targeted Therapy of Human Colonic and Pancreatic Cancer Xenografts with Potent Labetuzumab-SN-38 Immunoconjugates

Combined yeast-derived β-glucan with anti-tumor monoclonal antibody for cancer immunotherapy

Synthesis of N-succinimidyl 4-guanidinomethyl-3-[*I]iodobenzoate: a radio-iodination agent for labeling internalizing proteins and peptides

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