111In- and 225Ac-Labeled Cixutumumab for Imaging and α-Particle Radiotherapy of IGF-1R Positive Triple-Negative Breast Cancer (original) (raw)
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Scientific Reports
Overexpression of insulin growth factor receptor type 1 (IGF-1R) is observed in many cancers. Antibody drug conjugates (ADCs) with PEGylated maytansine (PEG6-DM1) show promise in vitro. We developed PEG6-DM1 ADCs with low and high drug to antibody ratios (DAR) using an anti-IGF-1R antibody cixutumumab (IMC-A12). Conjugates with low (cixutumumab-PEG6-DM1-Low) and high (cixutumumab-PEG6-DM1-High) DAR as 3.4 and 7.2, respectively, were generated. QC was performed by UV spectrophotometry, HPLC, bioanalyzer, and biolayer-interferometry. We compared the in vitro binding and internalization rates of the ADCs in IGF-1R-positive MCF-7/Her18 cells. We radiolabeled the ADCs with 111In and used microSPECT/CT imaging and ex vivo biodistribution to understand their in vivo behavior in MCF-7/Her18 xenograft mice. The therapeutic potential of the ADC was studied in vitro and in mouse xenograft. Internalization rates of all ADCs was high and increased over 48 h and EC50 was in the low nanomolar rang...
EJNMMI research, 2011
The aim of the present study was to explore the biodistribution, normal tissue toxicity, and therapeutic efficacy of the internalizing low-dose rate alpha-particle-emitting radioimmunoconjugate 227Th-trastuzumab in mice with HER2-expressing breast cancer xenografts. Biodistribution of 227Th-trastuzumab and 227Th-rituximab in nude mice bearing SKBR-3 xenografts were determined at different time points after injection. Tumor growth was measured after administration of 227Th-trastuzumab, 227Th-rituximab, cold trastuzumab, and saline. The toxicity of 227Th-trastuzumab was evaluated by measurements of body weight, blood cell, and clinical chemistry parameters, as well as histological examination of tissue specimens. The tumor uptake reached peak levels of 34% ID/g (4.6 kBq/g) 3 days after injection of 400 kBq/kg of 227Th-trastuzumab. The absorbed radiation dose to tumor was 2.9 Gy, while it was 2.4 Gy to femur due to uptake of the daughter nuclide 223Ra in bone; the latter already explor...
British Journal of Pharmacology, 2009
The studies described here are the first to evaluate the in vitro and in vivo properties of 111 In-CHX-A″-panitumumab for radioimmunotherapy (a-and b --emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography). Experimental approach: Twenty-seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX-A″-DTPA (diethylenetriamine-pentaacetic acid) and radiolabelled with 111 In. Immunoreactivity of the CHX-A″-DTPA-panitumumab and 111 In-CHX-A″-DTPA-panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by g-scintigraphy.
In this work Nimotuzumab (monoclonal antibody, recognizes the EGF-R) was radiolabeled with 177 Lu as a potential cancer therapy radiopharmaceutical. In-vitro cell binding studies and in-vivo biodistribution and imaging studies were performed to determine the radiochemical stability, targeting specificity and pharmacokinetics of the 177 Lu-labeled antibody. Nimotuzumab was derivatized with DOTA-NHS at room temperature for 2 hours. DOTA-Nimotuzumab was radiolabeled with 177 LuCl 3 (15 MBq/mg) at 37ºC for 1 h. The radiochemical purity was assessed by ITLC, silica gel and by RP-HPLC. Binding specificity studies were performed with EGF-R positive A431 human epithelial carcinoma and EGF-R negative MDA-MB-435 breast carcinoma cells. Biodistribution studies were performed in healthy female CD-1 mice at 1 h, 4 h, 24 h, and A431 xenografted nude mice at 10 min, 1 h, 4 h, 24 h, 48 h, and 96 h. SPECT-CT imaging studies were performed in A431 xenografted mice at 24 h post injection. DOTA-Nimotuzumab was efficiently labeled with 177 LuCl 3 at 37˚C. The in vitro stability of labeled product was optimal over 24 h in buffered saline and mouse serum. Specific recognition of EGF-R by 177 Lu-DOTA-Nimotuzumab was observed in A431 cell binding studies. Biodistribution studies demonstrated increasing tumor uptake of 177 Lu-DOTA-Nimotuzumab over time, with tumor to muscle ratios of 6.26, 10.68, and 18.82 at 4 h, 24 h, and 96 h post injection. Imaging of A431 xenografted mice showed high uptake in th e tumor. 177 Lu-DOTA-Nimotuzumab has the potential to be a promising therapy agent, which may be useful in the treatment of patients with EGF-R positive cancer.
Cancer Biotherapy & Radiopharmaceuticals, 2010
Purpose: The purposes of this study were to evaluate the organ biodistribution, pharmacokinetics, immunogenicity, and tumor uptake of 111 Indium ( 111 In)-MxDTPA-trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers and to determine whether 90 Y-MxDTPAtrastuzumab should be evaluated in subsequent clinical therapy trials. Experimental Design: Patients with HER2-overexpressing breast cancers who were to undergo planned trastuzumab therapy first received unlabeled trastuzumab (4-8 mg/kg IV), followed 4 hours later by 5 mCi 111 In-MxDTPA-trastuzumab (10 mg antibody). Serial blood samples, 24-hour urine collections, and nuclear scans were performed at defined time points for 7 days. Results: Eight (8) patients received 111 In-MxDTPA-trastuzumab, which was well tolerated with no adverse sideeffects. Three (3) of 7 patients with known lesions demonstrated positive imaging on nuclear scans. No antiantibody responses were observed for 2 months postinfusion. Organ doses (cGy/mCi) assuming radiolabeling with 90 Y were 19.9 for heart wall, 17.6 for liver, 4.6 for red marrow, and 2.8 for the whole body. Tumor doses ranged from 24 to 172 cGy/mCi. Conclusions: In summary, results from this study indicate that 90 Y-MxDTPA-trastuzumab is an appropriate agent to evaluate in therapy trials. No evidence of an immune response to 111 In-MxDTPA-trastuzumab was detected, predicting for the ability to administer multiple cycles. With the exception of cardiac uptake, pharmacokinetics and organ biodistribution were comparable to other 90 Y-labeled monoclonal antibodies previously evaluated in the clinic. Cardiac uptake was comparable to hepatic uptake and therefore predicted to not be prohibitively high as to result in dose-limiting cardiotoxicity.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2004
This study reports on the in vitro evaluation, biodistribution, and dosimetry of (123)I-labeled monoclonal antibody (mAb) 14C5, a new antibody-based agent proposed for radioimmunodetection of tumor growth and metastasis in vivo. (123)I-mAb 14C5 was prepared by direct iodination and tested for stability in vitro. Binding assays were performed on human SK-BR-3 and HeLa carcinoma cells to investigate the antigen expression, antibody affinity, and kinetics of tracer binding. For the biodistribution and dosimetry study, 3- to 4-wk-old NMRI mice were injected intravenously with (123)I-mAb 14C5 (148.0 +/- 7.4 kBq per mouse) and killed at preset time intervals. Organs, blood, urine, and feces were counted for radioactivity uptake, and the data were expressed as the percentage injected dose per gram tissue (%ID/g tissue) or %ID. The MIRDOSE3.0 program was applied to extrapolate the estimated absorbed radiation doses for various organs to the human reference adult. (123)I-mAb 14C5 was obtaine...
Trastuzumab and its radioimmunoconjugates in treatment of cancer
2016
Monoclonal antibodies are new type of targeted anticancer therapy, which achieve specificity, selectivity and localization in tumor cells. There are many naked antibodies and immunoconjugates commercially approved for different types of cancer (Mehren et al., 2003). In order to improve specificity and selectivity of cytotoxic drugs and toxins, monoclonal antibodies are used for formulation of immunoconjugates. Many efforts are done to develop stable immunoconjugates of trastuzumab with various drugs, toxins and radioisotopes to improve the general conditions of the patients (Sharkey and Goldenberg, 2006). The aim of this paper is to focus on current achievements in the formulation of radioimmunoconjugates of HER2-targeting trastuzumab.
Optimization of Radioimmunotherapy of Solid Tumors: Biological Impediments and Their Modulation
Clinical Cancer Research, 2007
In contrast to the overwhelming success of radiolabeled antibodies in treating hematologic malignancies, only modest success has been achieved in the radioimmunotherapy of solid tumors. One of the major limitations in successful application of radioimmunotherapy is the large molecular size of the intact immunoglobulin that results in prolonged serum half-life and poor tumor penetration and uptake.With the advent of antibody engineering, small molecular weight antibody fragments exhibiting improved pharmacokinetics and tumor penetration have been generated. However, their clinical application has been limited by suboptimal tumor uptake and short tumor residence time. There is a greater realization that optimization of the molecular size of the antibodies alone is not sufficient for clinical success of radioimmunotherapy. In addition to their size, radiolabeled antibodies encounter other impediments before reaching their target antigens expressed on the cell surface of solid tumors. Some of the barriers include poor blood flow in large tumors, permeability of vascular endothelium, elevated interstitial fluid pressure of tumor stroma, and heterogeneous antigen expression. Recent research has considerably improved our understanding and appreciation of these forces, and the new wave of optimization strategies involves the use of biological modifiers to modulate the impediments posed by solid tumors. In combination with radiolabeled antibodies, various agents are being used to improve the tumor blood flow, enhance vascular permeability, lower tumor interstitial fluid pressure by modulating stromal cells and extracellular matrix components, up-regulate the expression of target antigens, and improve the penetration and retention of the radiopharmaceuticals. This review outlines ongoing research efforts involving biological modifiers to optimize the uptake and efficacy of radiolabeled antibodies for the treatment of solid tumors.
Evaluation of 225 Ac for Vascular Targeted Radioimmunotherapy of Lung Tumors
Cancer Biotherapy & Radiopharmaceuticals, 2000
Several alpha particle emitting radioisotope s have been studied for use in radioimm unotherapy. Ac-225 has the potential advantages of a relatively long half life of 10 days, and a yield of 4 alpha emissions in its decay chain with a total energy release of , 28 MeV. A new, 12 coordination site chelating ligand, HEHA, has been chemically modified for coupling to targeting proteins without loss of chelating ability. HEHA was coupled with MAb 201B which binds to thrombomod ulin and accumulates efficiently in murine lung. Ac-225 was bound to the HEHA-MAb 201B conjugate and injected into BALB/c mice bearing lung tumor colonies of EMT-6 mammary carcinoma. Biodistribution data at 1 and 4 h postinjection indicated that, as expected, 225 Ac was delivered to lung efficiently (. 300 % ID/g). The 225 Ac was slowly released from the lung with an initial t 1/2 5 49 h, and the released 225 Ac accumulated in the liver. Injection of free HEHA was only partially successful in scavenging free 225 Ac. In addition to the slow release of 225 Ac from the chelate, data indicated that decay daughters of 22 5 Ac were also released from the lung. Immediately after organ harvest, the level of 21 3 Bi, the third alpha-decay daughter, was found to be deficient in the lungs and to be in excess in the kidney, relative to equilibrium values. Injected doses of 22 5 Ac MAb 201B of 1.0 m Ci, delivering a minimum calculated absorbed dose of about 6 Gy to the lungs, was effective in killing lung tumors, but also proved acutely radiotoxic. Animals treated with 1.0 m Ci or more of the 225 Ac radioconjuga te died of a wasting syndrome within days with a dose dependent relationship. We conclude that the potential for 225 Ac as a radioimm unotherapeut ic agent is compromised not only by the slow release of 225 Ac from the HEHA chelator, but most importantly by the radiotoxicity associated with decay daughter radioisotope s released from the target organ.
Dose Escalation and Dosimetry of First-in-Human α Radioimmunotherapy with 212Pb-TCMC-Trastuzumab
Journal of Nuclear Medicine, 2014
Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity, and tumor response of intraperitoneal 212 Pb-TCMCtrastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2)expressing malignancy. Methods: In a standard 3 1 3 phase 1 design for dose escalation, 212 Pb-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies. Results: Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m 2) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n 5 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time). Non-decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5μSv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative. Conclusion: Five dose levels of intraperitoneal 212 Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.