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Abstract

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.

Microarrays of 41 Human Tumor Cell Lines for the Characterization of New Molecular Targets: Expression Patterns of Cathepsin B and the Transferrin Receptor

“…Many drug-targeting approaches employ receptor-mediated endocytosis for enhanced drug uptake (e.g. via the transferrin receptor) or the expression of tumor-associated proteases, such as cathepsin B, for prodrug cleavage and activation [11, 14, 16, 19]. Artemisinin-tagged holotransferrin, for instance, has recently been shown to inhibit growth of the leukemia cell line MOLT4 [12].…”

“…Since it facilitates endocytosis of its ligands, it has been used for targeting transferrin- or antibody-linked compounds. One of these agents, a diphtheria toxin linked to human transferrin, is being evaluated in a phase II clinical trial [11], while others have recently been developed, e.g. artemisinin-tagged holotransferrin [12], an avidin-linked anti-CD71 antibody [13], immunoliposomes [14] or neutralizing antibodies [15, 16].…”

The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics

“…A number of targeted toxins have been developed for potential use in GB patients and several have advanced to human clinical trials. 124,125 Some of the “GB tumor-specific” cell surface proteins targeted by these constructs include podoplanin, 126 glycoprotein NMB, 127 ephrin type-A receptor 2 (EphA2), 128 urokinase plasminogen activator receptor (uPAR), 129,130 transferrin receptor (TfR), 131 EGFR, 132,133 the constitutively activated EGFRvIII deletion mutant, 134 IL-4Rα, 135,136 and IL-13Rα2. 86,137,138 Bispecific constructs targeting two different GB cell surface proteins have also been described.…”

Convection Enhanced Drug Delivery of Novel Therapeutic Agents to Malignant Brain Tumors

“…Tf-CRM107, better known as TransMID-107 (Trans-MID; Xenova Group, Slough, Berkshire, United Kingdom), is fusion protein consisting of human transferrin (Tf) with a modified form of diphtheria named CRM-107, which lacks receptor binding [51]. This agent attacks tumor cells using the transferrin receptor (TfR) which mediates cellular uptake of iron in cells [52].…”

“…The median survival time for all 44 patients was 37 weeks. Of the 34 patients who could be evaluated for the analysis, there was a statistically significant response rate of 35% (5 complete responders and 7 partial responders) [51].…”