The transferrin receptor part I: Biology and targeting with cytotoxic antibodies for the treatment of cancer.

We investigated regional therapy of recurrent malignant brain tumors with transferrin-CRM107, a conjugate of human transferrin (Tf) and a genetic mutant of diphtheria toxin (CRM107) that lacks native toxin binding. Physiological barriers to delivering proteins to tumor and surrounding infiltrated brain were circumvented with high-flow interstitial microinfusion. At least a 50% reduction in tumor volume on magnetic resonance imaging (MRI) occurred in 9 of 15 patients who could be evaluated (60%), including two complete responses. Peritumoral toxicity developed 1–4 weeks after treatment in three of three patients at 1.0 μg/ml, but in zero of nine patients treated at lower concentrations. No symptomatic systemic toxicity occurred. Regional perfusion with Tf-CRM107 produces tumor responses without systemic toxicity in patients with malignant brain tumors refractory to conventional therapy. Direct interstitial infusion can be used successfully to distribute a large protein in the tumor and infiltrated brain surrounding the tumor.

Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors

Intraspecific human-human cell hybrids provide a stable model system with which to investigate the genetic control of transformed and tumorigenic phenotypes. Using this system it has been shown that these phenotypes are under separate genetic control. Furthermore, the tumorigenic phenotype can be complemented by fusion of different tumorigenic cells, resulting in nontumorigenic hybrids. This system also provides information on the control of differentiated function. Molecular cytogenetic techniques should reveal the nature of the chromosomal control of neoplastic transformation.

Human cell hybrids: analysis of transformation and tumorigenicity

Biosynthesis of the human transferrin receptor in cultured cells.

The authors review the preclinical and clinical results of the ligand-targeted toxin conjugate Transferrin-CRM107 (Tf-CRM107), for the treatment of malignant gliomas. Tf-CRM107 is a conjugate protein of diphtheria toxin with a point mutation (CRM107) linked by a thioester bond to human transferrin (Tf). This conjugate exhibits potent cytotoxicity in vitro against mammalian cells expressing the transferrin receptor with activity at picomolar concentrations. Phase I clinical trial results demonstrated that Tf-CRM107, delivered via a high-flow convection method utilizing stereotactically placed catheters, produced tumor response in patients with malignant brain tumors refractory to conventional therapy without severe neurologic or systemic toxicity. The results of a Phase II study are also summarized. Tf-CRM107 treatment results in complete and partial tumor response without severe toxicity in 35% of the evaluable patients. These data warrant a Phase III study as well as continued research in the field of targeted toxin therapy. Future directions of research include optimizing Tf-CRM107 delivery to targeted brain regions, and improving the treatment efficacy by combining with other toxin conjugates targeted to different receptors.

Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas.

A transferrin receptor was demonstrated in tumor tissue from 10 patients with breast carcinoma and one patient with breast sarcoma. Binding studies were conducted by measuring the amont of 1251-transferrin binding to microsomal preparations of the tumor tissue. Elevated levels of specific transferrin binding were found in the tumors with a range of 11-35% of bound transferrin, whereas microsomes prepared from non-neoplastic breast tissue samples bound only 2.3% and 2.4% of the transferrin. Scatchard analysis of binding studies conducted with tissues from a breast cancer and from a breast sarcoma indicate that the receptor has a Ka = 9.0 x 10(8)M. The binding site is specific for transferrin, as studies show that non-radioactive transferrin displaced labelled transferrin, while human IgG and human albumin did not. The receptor-transferrin complex was precipitated from a detergent extract of the breast sarcoma with antiserum to human transferrin. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis of the immunoprecipitate gave a polypeptide of M 90,000 daltons, which is of similar molecular weight found for the putative transferrin receptor in all of a series of human cultured cell lines previously examined.

Demonstration of the transferrin receptor in human breast cancer tissue. Potential marker for identifying dividing cells.

The screening of a series of 11 metastatic breast tumors for the presence of the placental isoenzyme of alkaline phosphatase (EC 3.1.3.1) by RIA revealed one strong producer. The alkaline phosphatase of this tumor was characterized with respect to its immunochemical cross-reactivity, inhibition by L-phenylalanine and levamisole, subunit molecular weight (Mr) and isoelectric point (pl) in two-dimensional electrophoresis, and one-dimensional peptide map. In all parameters of the characterization, the tumor alkaline phosphatase was similar to placental alkaline phosphatase, except for subunit molecular weight which was slightly lower (60,000 versus 64,000 for the placental isoenzyme). No strong placental alkaline phosphatase producers were found among 16 primary tumors examined by RIA. The screening of patients' sera for the placental alkaline phosphatase using RIA indicated elevated levels over post-menopausal controls in 20% of the metastatic patients. Only 3% of the primary patients had elevated serum levels. These results suggest that the placental isoenzyme of alkaline phosphatase may be a useful tumor marker for recurrent breast cancer.

Demonstration of placental alkaline phosphatase in human breast cancer

In an ongoing longitudinal study for tumor markers in breast cancer patients, levels of placental alkaline phos-phatase (PAP) measured by RIA were found to be elevated in 34% of patients who smoked cigarettes as opposed to 5 % of non-smoking subjects A normal range was established (0-214 ng/ml) using healthy non-smoking females In an expanded analysis by disease state, PAP levels were found to be elevated significantly (p<002) in the smoking groups of each category This isoenzyme, when detected at elevated serum levels by RIA, was enzymatically active in 48% of the patients as analyzed by immunoenzymatic assay One smoker with high PAP levels discontinued smoking following a myocardial infarction Her PAP levels returned to normal within 2 months

Elevation of serum placental alkaline phosphatase levels in cigarette smokers

Serum and tumor tissue from breast cancer patients were evaluated for the presence of alpha subunit of hCG, by means of the specific radioimmunoassay. Elevated serum levels occurred in 0/50 (0%) of normal female controls, 1/17 (6%) of patients with benign breast disease, 3/53 (6%) of patients with primary breast cancer, and 12/84 (14%) of patients with metastatic breast cancer. Cytosols from 10/56 (18%) primary tumors and 10/37 (28%) metastatic tumors were found to contain the alpha subunit. Comparison of serum and tumor cytosol levels in nine patients with metastatic disease showed a correspondence between elevated cytosol levels and elevated serum levels. No similar correspondence in 25 patients with primary disease was observed. Alpha subunit was isolated from one tumor cytosol and was characterized with respect to its immunochemical cross-reactivity and molecular weight as compared with native alpha subunit from hCG. For both parameters, the native and ectopic alpha subunit were found to be identical.

Distribution and characterization of alpha hCG in the serum and tumor cytosol of patients with breast cancer.

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Demonstration of the transferrin receptor in human breast cancer tissue. Potential marker for identifying dividing cells.

Demonstration of placental alkaline phosphatase in human breast cancer

Elevation of serum placental alkaline phosphatase levels in cigarette smokers

Distribution and characterization of alpha hCG in the serum and tumor cytosol of patients with breast cancer.