title: Pharmacokinetics, biodistribution, and dosimetry of specific and control radiolabeled monoclonal antibodies in patients with primary head and neck squamous cell carcinoma.
abstract: The pharmacokinetics, biodistribution, and dosimetry of an IgG1 radiolabeled anti-mucin mAb (HMFG1) and an isotype-matched control (4D513) were studied in 29 patients with primary head and neck squamous cell carcinoma. Patients were given injections at 3 fixed time points prior to surgery, i.e., 24 (n = 12), 48 (n = 9), or 72 (n = 8) h. They were subsequently classified into two groups based on their immunohistochemical positivity for polymorphic epithelial mucin. Fourteen patients (48%) were positive, 5 of which were studied with both antibodies; and 15 patients were negative (52%), 7 of which were studied with both antibodies. There was no significant difference in serum pharmacokinetics and cumulative urinary clearance of the two antibodies. There was no significant difference in overall normal tissue uptake of specific and control antibody; however, when each component of the normal tissue category was analyzed individually, there was a significantly increased uptake of HMFG1 in mucosa as compared to control antibody. Immunohistochemical studies revealed positive staining of mucosa with HMFG1. There was significantly increased uptake of specific antibody in antigen-positive tumors as compared to uptake of control antibody (P < 0.02). A tendency for less label loss over time from positive tumors as compared to control was documented. Absolute antibody uptake and tumor/normal tissue ratios demonstrated significant overlap in individual patients from each category depending on the specific ratio (e.g., tumor/adipose tissue) or time point studied; hence arbitrary cutoff values could not be recommended as indicators of specific uptake. Specificity and localization indices were the most reproducible indicators of specific localization. Areas under the curve were calculated for all tissues, and local dosimetry for the two beta-emitting isotopes 131I and 90Y is presented. The Deq values for antigen-positive tumors were 2.9 cGy/mCi for 131I and 9.0 cGy/mCi injected for 90Y. For antigen-negative tumors these values were significantly lower at 0.83 and 2.4 cGy/mCi of 131I and 90Y, respectively. Bone marrow Deq was calculated to be 0.87 cGy/mCi of 131I-HMFG1 injected. Because the purpose of our ongoing research is to assess the therapeutic potential of the combination of radiolabeled antibody and external radiotherapy, detailed dose calculation to local dose-limiting tissues is required. Deq to mucosa was calculated to be 1.1 and 3.8 cGy/mCi of injected 131I and 90Y, respectively. We conclude that a 9-10-Gy dose increment may be achieved in two administrations of 150 mCi of 131I-HMFG1 during a course of external radiotherapy. This may lead to improved control of local disease in patients with head and neck cancer.
authors.affiliation: Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Maraveyas
authors.forename: N
authors.initials: N
authors.lastname: Stafford
authors.forename: G
authors.initials: G
authors.lastname: Rowlinson-Busza
authors.forename: J S
authors.initials: JS
authors.lastname: Stewart
authors.forename: A A
authors.initials: AA
authors.lastname: Epenetos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D001853:Bone Marrow / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000532:radiotherapy* / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000532:radiotherapy* / Q000601:surgery; D006801:Humans; D000922:Immunotoxins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007457:Iodine Radioisotopes; D008099:Liver / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D008894:Milk Proteins / Q000276:immunology; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D007457:Iodine Radioisotopes; D008894:Milk Proteins