Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers

Garambois, Véronique; Fabienne, Glaussel; Foulquier, Elodie; Ychou, Marc; Pugnière, Martine; Luo, Robin X.; Bezabeh, Binyam; Pèlegrin, André

doi:10.1186/1471-2407-4-75

Cited by 13 publications

(6 citation statements)

References 39 publications

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“…In order to receive uniform parameters as from the MORFF measurements we decided to apply the 1:1 (Langmuir) fit. The determined values for the equilibrium constants are well comparable with results determined by Kure et al [27] (hInsulin), Seet et al [28] (hEotaxin), and Garambois et al [29] (hCEA). In contrast, the kinetic parameters obtained by SPR do not support the results of our MORFF measurements.…”

Section: Discussionsupporting

confidence: 89%

Magneto-optical relaxation measurements for the characterization of biomolecular interactions

Aurich¹,

Glöckl²,

Romanus³

et al. 2006

J. Phys.: Condens. Matter

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Measurements of the magneto-optical relaxation of ferrofluids (MORFF) were applied as a novel homogeneous immunoassay for the investigation of biomolecular interactions. The technique is based on magnetic nanoparticles (MNP) functionalized with antibodies. The relaxation time of the optical birefringence that occurs when a pulsed magnetic field is applied to the nanoparticle suspension depends on the particle size. This enables the detection of particle aggregates formed after the addition of the antigen coupling partner. MORFF size measurements on the original ferrofluid and its fractions obtained by magnetic fractionation are comparable with results from other methods such as atomic force microscopy and photon correlation spectroscopy. In kinetic studies, the binding properties of five antigens and their polyclonal antibodies were investigated: human immunoglobulin G (hIgG), human immunoglobulin M (hIgM), human Eotaxin (hEotaxin), human carcinoembryonic antigen (hCEA), and human insulin (hInsulin). The enlargement of the relaxation time observed during the coupling experiments is expressed in terms of a size distribution function, which includes MNP monomers as well as aggregates. The kinetic process can be described by a model of stepwise polymerization. The kinetic parameters obtained are compared to results of surface plasmon resonance measurements.

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Section: Discussionsupporting

confidence: 89%

Magneto-optical relaxation measurements for the characterization of biomolecular interactions

Aurich¹,

Glöckl²,

Romanus³

et al. 2006

J. Phys.: Condens. Matter

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“…Future research should be geared toward humanized anti-CEA antibodies, such as 131 I-labetuzumab and 131 IhMN14. A fully human anti-CEA IgG2n has been developed at our center and is a promising candidate for RIT in intact form, as a F(ab ¶) 2 , or as a bispecific antibody (33). Other promising avenues include use of affinity enhancement systems with pretargeting bispecific mAb (34).…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Radioimmunotherapy Trial with Iodine-131–Labeled Anti–Carcinoembryonic Antigen Monoclonal Antibody F6 F(ab′)2 after Resection of Liver Metastases from Colorectal Cancer

Ychou

Azria

Menkarios

et al. 2008

Clinical Cancer Research

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Purpose: To evaluate the feasibility of radioimmunotherapy (RIT) with radiolabeled antiĉ arcinoembryonic antigen antibodies after complete resection of liver metastases (LM) from colorectal cancer. Patients and Methods: Twenty-two patients planned for surgery of one to four LM received a preoperative diagnostic dose of a 131 I-F(ab ¶) 2^l abeled anti-carcinoembryonic antigen monoclonal antibody F6 (8-10 mCi/5 mg). 131I-F(ab ¶) 2 uptake was analyzed using direct radioactivity counting, and tumor-to-normal liver ratios were recorded. Ten patients with tumor-to-normal liver ratios of >5 and three others were treated with a therapeutic injection I/50 mg F(ab ¶) 2 ] 30 to 64 days after surgery. Results: Median 131 I-F(ab ¶) 2 immunoreactivity in patient serum remained at 91% of initial values for up to 96 hours after injection. The main and dose-limiting-toxicity was hematologic, with 92 % and 85 % grades 3 to 4 neutropenia and thrombocytopenia, respectively. Complete spontaneous recovery occurred in all patients. No human anti-mouse antibody response was observed after the diagnosis dose; however, 10 of the 13 treated patients developed human anti-mouse antibody f3 months later. Two treated patients presented extrahepatic metastases at the time of RIT (one bone and one abdominal node) and two relapsed within 3 months of RIT (one in the lung and the other in the liver). Two patients are still alive, and one of these is diseasefree at 93 months after resection. At a median follow-up of 127 months, the median disease-free survival is 12 months and the median overall survival is 50 months. Conclusion: RIT is feasible in an adjuvant setting after complete resection of LM from colorectal cancer and should be considered for future trials, possibly in combination with chemotherapy, because of the generally poor prognosis of these patients.Surgical resection is the most effective therapy for isolated liver metastases (LM) from colorectal cancer (CRC; refs. 1 -4) and offers the only possibility of cure in these patients. When complete resection is achieved, 5-year survival rates ranging from 25% to 41% have been reported (2, 3, 5 -7). However, approximately two-thirds of patients relapse, often in the first 2 years, demonstrating the need for efficient postoperative therapies capable of sterilizing microscopic disease. Although chemotherapy in this setting has enhanced disease-free survival (DFS), it has not clearly shown a survival advantage. Efforts have thus been focused on immunotherapy and radioimmunotherapy (RIT) with native or radiolabeled monoclonal antibodies (mAb) based on impressive results in the treatment of non -Hodgkin lymphoma (8 -10). Studies of radiolabeled mAb in the adjuvant setting of CRC or with small volume disease have been reported (11,12), although success with bulky, metastatic tumors from CRC has been limited (13 -15). At our institution, an initial phase I study involving patients with nonresectable and chemorefractory LM from CRC showed that the maximal tolerated dose of 131

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“…Several CEA-targeting antibodies have previously been labeled with various radionuclides and explored in vitro , in vivo , and in clinical trials, demonstrating promising results ( 10 – 12 , 20 , 21 ). T84.66 is a well-characterized anti-CEA murine IgG 1 monoclonal antibody (mAb) that does not cross-react with other members of the CEA gene family and has successfully been used for 111 In imaging of patients with primary colorectal adenocarcinomas ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer

Mohajershojai

Jha

Boström³

et al. 2022

Front. Oncol.

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Carcinoembryonic antigen (CEA) is an antigen that is highly expressed in colorectal cancers and widely used as a tumor marker. 131I and 90Y-radiolabeled anti-CEA monoclonal antibodies (mAbs) have previously been assessed for radioimmunotherapy in early clinical trials with promising results. Moreover, the heat shock protein 90 inhibitor onalespib has previously demonstrated radiotherapy potentiation effects in vivo. In the present study, a 177Lu-radiolabeled anti-CEA hT84.66-M5A mAb (M5A) conjugate was developed and the potential therapeutic effects of 177Lu-DOTA-M5A and/or onalespib were investigated. The 177Lu radiolabeling of M5A was first optimized and characterized. Binding specificity and affinity of the conjugate were then evaluated in a panel of gastrointestinal cancer cell lines. The effects on spheroid growth and cell viability, as well as molecular effects from treatments, were then assessed in several three-dimensional (3D) multicellular colorectal cancer spheroid models. Stable and reproducible radiolabeling was obtained, with labeling yields above 92%, and stability was retained at least 48 h post-radiolabeling. Antigen-specific binding of the radiolabeled conjugate was demonstrated on all CEA-positive cell lines. Dose-dependent therapeutic effects of both 177Lu-DOTA-M5A and onalespib were demonstrated in the spheroid models. Moreover, effects were potentiated in several dose combinations, where spheroid sizes and viabilities were significantly decreased compared to the corresponding monotherapies. For example, the combination treatment with 350 nM onalespib and 20 kBq 177Lu-DOTA-M5A resulted in 2.5 and 2.3 times smaller spheroids at the experimental endpoint than the corresponding monotreatments in the SNU1544 spheroid model. Synergistic effects were demonstrated in several of the more effective combinations. Molecular assessments validated the therapy results and displayed increased apoptosis in several combination treatments. In conclusion, the combination therapy of anti-CEA 177Lu-DOTA-M5A and onalespib showed enhanced therapeutic effects over the individual monotherapies for the potential treatment of colorectal cancer. Further in vitro and in vivo studies are warranted to confirm the current study findings.

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Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers

Abstract: Background: Human monoclonal antibodies (MAbs) are needed for colon cancer radioimmunotherapy (RIT) to allow for repeated injections. Carcinoembryonic antigen (CEA) being the reference antigen for immunotargeting of these tumors, we developed human anti-CEA MAbs.

Cited by 13 publications

References 39 publications

Magneto-optical relaxation measurements for the characterization of biomolecular interactions

Magneto-optical relaxation measurements for the characterization of biomolecular interactions

Adjuvant Radioimmunotherapy Trial with Iodine-131–Labeled Anti–Carcinoembryonic Antigen Monoclonal Antibody F6 F(ab′)2 after Resection of Liver Metastases from Colorectal Cancer

In Vitro Characterization of 177Lu-DOTA-M5A Anti-Carcinoembryonic Antigen Humanized Antibody and HSP90 Inhibition for Potentiated Radioimmunotherapy of Colorectal Cancer

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