TF2 bispecific antibody pretargeted therapy prolongs survival in animal model of human colonic cancer

Jun 10 2010

Results From 2 Preclinical Studies Presented at 2010 Annual Meeting of the Society of Nuclear Medicine (SNM)

Two Additional Studies on Novel F-18 Labeling of Peptides Also Reported

Immunomedics, Inc. (Nasdaq: IMMU), a biopharmaceutical company focused on developing monoclonal antibodies to treat cancer and other serious diseases, today announced that pretargeted therapy with TF2, a bispecific antibody against carcinoembryonic antigen (CEA) and a small peptide, delayed tumor growth and prolonged survival in an animal model of human colonic cancer.

Developed with IBC Pharmaceuticals, Inc., the Company's majority-owned subsidiary, pretargeting aims at optimizing antibody-directed radiation therapy by separating the administration of the antibody from the delivery of radiation. As a result, the signal at the tumor relative to non-tumor tissues is improved and the amount of the therapeutic in the tumor is selectively enhanced. More importantly, increased amount of radiation can be administered without concomitantly raising the levels of deleterious side-effects.

TF2 is a new generation of bispecific antibodies constructed using the Company's patented Dock-and-Lock (DNL) protein engineering platform technology. It is currently in two early Phase I studies in patients with colorectal cancer. 

The objective of this preclinical study was to assess the efficacy and toxicity of TF2 for pretargeted radiation therapy in animals bearing CEA-expressing human colonic tumors.  Pretargeted radiation therapy with TF2 extended median survival from 13 days in untreated animals to 65 days in one model, representing a 5-fold increase in survival, and from 25 days to 48 days in another model, an almost 2-fold increase in survival. Bone marrow and kidney toxicity was temporary and mild, with body weight remaining greater than 93% of baseline in all animals. These animal studies suggest that this treatment could be effective for colon cancer with limited toxicity.

TF2 was also the subject of a pretargeted imaging study reported earlier at the same conference. Entitled "Pretargeted immunoPET for imaging human colonic cancer in a mouse model," the study compared TF2 pretargeting with ¹⁸F-fluorodeoxyglucose (FDG-PET) for detecting CEA-expressing human colonic tumors growing in the peritoneum (abdomen) of animals. For this preclinical imaging study, a ⁶⁸Ga-labeled peptide was used in combination with TF2 to produce high tumor/background activity ratios (e.g., tumor/intestines 57.5±22.4) and within one hour, resulted in the clear visualization of small tumors (1.5 mm) as well as large (5.0 mm) lesions. Although the sensitivity of pretargeted PET imaging with TF2 and ⁶⁸Ga- or ¹⁸F-labeled peptides has yet to be evaluated in patients, the high tumor-to-background ratio and clear visualization of CEA-positive tumors on the PET/CT images in this study indicate that this method has the potential to be applicable clinically.

The Company recently reported a new method of attaching F-18 to a peptide by forming an aluminum-fluoride complex. In another presentation entitled, "Rapid, one-step, high-specific activity, radiolabeling of peptides with F-18 without HPLC purification," given earlier at this SNM annual meeting, the F-18 labeling efficiency was improved and the method was reduced to a simple kit. By using this F-18 kit, a pretargeting peptide was radiolabeled and purified within about 30 minutes with a high specific activity. The peptide was injected into nude mice bearing human colonic cancer, pretargeted with TF2. Specific tumor uptake was observed at 1 and 3 hours post-injection, with high tumor/non-tumor ratios (150±137, 89±75, 22±9, and 5.4±1.8 for blood, liver, scapula, and kidney, respectively) obtained at 1 hour.

A separate F-18 labeling study, "A new and rapid method of labeling peptides with F-18," which involved the peptide known as octreotide, was also presented at the conference. ¹⁸F-labeled octreotide was prepared within 45 minutes with acceptable yields. Biodistribution studies in mice bearing human pancreatic cancer showed rapid tumor uptake of ¹⁸F-labeled octreotide at 2 hours, which could be blocked by an excess of unlabeled peptide, proving specific targeting. Moreover, PET/CT scans showed excellent tumor delineation, as well as some retention in the kidney cortex.

The two F-18 labeling projects described were supported in part by grants from the National Institutes of Health. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.