Pseudomonas exotoxin A (PE) linked to the F(ab')2 fragment of 1H10, a murine monoclonal antibody recognizing a carbohydrate epitope of a glycoconjugate expressed on the surface of human cervical carcinoma tumor cells, was evaluated for in vitro and in vivo activity. PE can kill cells by ADP-ribosylating elongation factor 2 thus inhibiting protein synthesis. Disulfide- as well as thioether-linke...

Successful treatment of many patients with osteosarcoma requires more effective chemotherapy. Since new agents are needed, we have developed an immunotoxin using TP-3, an IgG2b mAb which recognizes human and canine osteosarcomas and budding capillaries of tumors. The plant hemitoxin, pokeweed antiviral protein (PAP), was conjugated to TP-3 to produce an immunotoxin highly active against osteosa...

PURPOSE To investigate mesothelin as a new target for immunotherapy in lung cancer. EXPERIMENTAL DESIGN Mesothelin mRNA and protein expression were assessed by reverse transcription-PCR, immunoblotting, and immunohistochemistry in human lung cancer specimens. Expression was also characterized in human lung cancer cell lines by flow cytometry and immunoblotting. The SS1P immunotoxin specific f...

Pseudomonas exotoxin (PE)-based immunotoxins (antibody-toxin fusion proteins) have achieved frequent complete remissions in patients with hairy cell leukemia but far fewer objective responses in other cancers. To address possible mechanisms of resistance, we investigated immunotoxin activity in a model system using the colon cancer cell line, DLD1. Despite causing complete inhibition of protein...

The anticancer strategy underlying the use of immunotoxins is as follows: the cancer-binding domain delivers the toxin to a cancer cell, after which the toxin enters and kills the cell. TGFα-PE38 is an immunotoxin comprising transforming growth factor alpha (TGFα), a natural ligand of epidermal growth factor receptor (EGFR), and a modified Pseudomonas exotoxin A (PE38) lacking N terminal cell-b...

We have recently reported that an immunotoxin targeting mesothelin produced durable major tumor regressions in patients with extensive treatment-refractory mesothelioma. These unprecedented tumor responses have prompted us to review how mesothelin was discovered and the advances that led to these tumor responses. This review is not comprehensive but focuses on major developments over the past 2...

MUC1 is a mucin family protein, overexpressed in more than 90% of breast cancers in an underglycosylated form, exposing the core peptides of the extracellular domain that act as a potential target for antibody-mediated therapy. We have developed an anti-MUC1 scFv antibody from a phage library of mice immunized with synthetic peptide MUC1-variable number of tandem repeats. MUC1 binding phages we...

We present a novel methodology to visualize tumor cells directly in a whole mouse. This technique combines immunohistochemistry with whole mouse sectioning. It lets one see the exact distribution of tumor cells throughout an animal and how effectively these cells are eliminated by cancer therapeutics. We used this technique to assess the efficacy of a T cell-specific immunotoxin in a severe com...

Fifteen patients with refractory B-cell lymphoma were treated in a Phase I dose escalation clinical trial with a highly potent immunotoxin consisting of the Fab' fragment of a monoclonal anti-CD22 antibody (RFB4) coupled to chemically deglycosylated ricin A chain. All patients had low, intermediate, or high grade non-Hodgkin's lymphoma. The immunotoxin was administered i.v. in two to six doses ...

Fifteen patients with refractory B-cell lymphoma were treated in a Phase I dose escalation clinical trial with a highly potent immunotoxin consisting of the Fab' fragment of a monoclonal anti-CD22 antibody (RFB4) coupled to chemically deglycosylated ricin A chain. All patients had low, intermediate, or high grade non-Hodgkin's lymphoma. The immunotoxin was administered i.v. in two to six doses ...