L-Tyrosine Confers Residualizing Properties to a d-Amino Acid-Rich Residualizing Peptide for Radioiodination of Internalizing Antibodies.

Purpose: The aims of the study were to develop and evaluate a novel residualizing peptide for labeling internalizing antibodies with (124)I to support clinical development using immuno-positron emission tomography (PET).

Methods: The anti-epidermal growth factor receptor antibody ch806 was radiolabeled directly or indirectly with isotopes and various residualizing peptides. Azido-derivatized radiolabeled peptides were conjugated to dibenzylcyclooctyne-derivatized ch806 antibody via click chemistry.

Cross-species analysis of Fc engineered anti-Lewis-Y human IgG1 variants in human neonatal receptor transgenic mice reveal importance of S254 and Y436 in binding human neonatal Fc receptor.

IgG has a long half-life through engagement of its Fc region with the neonatal Fc receptor (FcRn). The FcRn binding site on IgG1 has been shown to contain I253 and H310 in the CH2 domain and H435 in the CH3 domain. Altering the half-life of IgG has been pursued with the aim to prolong or reduce the half-life of therapeutic IgGs.

Molecular imaging of death receptor 5 occupancy and saturation kinetics in vivo by humanized monoclonal antibody CS-1008.

Purpose: CS-1008 (tigatuzumab; phase I/II), an antihuman death receptor 5 (DR5) agonist, induces apoptosis and has cytotoxic activity against human cancer cell lines. This study reports on the preclinical validation of (111)In-labeled anti-DR5 humanized antibody CS-1008 as a diagnostic tool to study the DR5 occupancy in patients with cancer and establish dose ranges for receptor saturation kinetics in vivo.

Experimental Design: CS-1008 was radiolabeled and characterized for DR5 binding and labeling efficiency on TRAIL-sensitive DR5-positive colorectal cancer cells (COLO 205 and WiDr).

Immuno-PET quantitation of de2-7 epidermal growth factor receptor expression in glioma using 124I-IMP-R4-labeled antibody ch806.

Unlabelled: Overexpression, activation, and mutations of the epidermal growth factor receptor (EGFR) are commonly found in solid tumors. The aim of this study was to develop a PET-based method for detecting the constitutively active mutant de2-7 EGFR, which is associated with disease progression and resistance to chemotherapy and radiotherapy in glioma.

Methods: The chimeric antibody ch806, which selectively binds an epitope of the EGFR that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor, was conjugated to the radiohalogen (124)I via the residualizing ligand IMP-R4, and in vitro properties were characterized.

Investigation of hypoxia and carbonic anhydrase IX expression in a renal cell carcinoma xenograft model with oxygen tension measurements and ¹²⁴I-cG250 PET/CT.

Objectives: In tumors, hypoxia stimulates angiogenesis and correlates with treatment resistance and poor prognosis. We have previously demonstrated hypoxia in human renal cell carcinoma (RCC) via direct oxygen probe measurements. Carbonic anhydrase IX (CA IX) is a protein stimulated by hypoxia and involved in angiogenesis, and is a potential tumor target for imaging and therapies using cG250, a monoclonal antibody that recognizes CAIX.

Radioimmunotherapy with alpha-particle emitting 213Bi-C-functionalized trans-cyclohexyl-diethylenetriaminepentaacetic acid-humanized 3S193 is enhanced by combination with paclitaxel chemotherapy.

Purpose: Previous experience in solid tumor radioimmunotherapy studies has indicated that greatest therapeutic efficacy is achieved in the treatment of small-volume disease. alpha-Particle-emitting radioisotopes possess several physical characteristics ideally suited to the treatment of minimal residual disease. Therefore, we have investigated the efficacy of the alpha-particle-emitting bismuth-213 (213Bi) radioimmunotherapy using the humanized anti-Lewis Y (Ley) monoclonal antibody humanized 3S193 (hu3S193).

Enhanced efficacy of 90Y-radiolabeled anti-Lewis Y humanized monoclonal antibody hu3S193 and paclitaxel combined-modality radioimmunotherapy in a breast cancer model.

Unlabelled: Radioimmunotherapy (RIT) of solid tumor is often limited in efficacy because of restrictions in achieved tumor dose. In an effort to overcome this, the combination of RIT with other therapeutic modalities was investigated in an animal model of breast carcinoma. The rationale for this combined-modality RIT (CMRIT) was to increase the therapeutic efficacy of RIT through the use of paclitaxel to arrest cells in the radiosensitive G(2)/M phase of the cell cycle.

Enhanced efficacy of radioimmunotherapy with 90Y-CHX-A''-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478.

Purpose: Monoclonal antibodies and tyrosine kinase inhibitors specific for the epidermal growth factor receptor (EGFR) have been shown to enhance the effect of external beam radiation on EGFR-positive tumors. The effect of EGFR signaling abrogation by EGFR tyrosine kinase inhibitor on the efficacy of radioimmunotherapy has not been reported previously. This study investigated the effect of EGFR tyrosine kinase inhibition on the efficacy of radioimmunotherapy in a human cancer xenograft model.

Phase I trial of 131I-huA33 in patients with advanced colorectal carcinoma.

Purpose: Humanized monoclonal antibody A33 (huA33) targets the A33 antigen which is expressed on 95% of colorectal cancers. A previous study has shown excellent tumor-targeting of iodine-131 labeled huA33 (131I-huA33). Therefore, we did a phase I dose escalation trial of 131I-huA33 radioimmunotherapy.