Anti-TGF-β Reduces RT-Induced Lung Injury in Animals

DENVER-An antibody to transforming growth factor-β (TGF-β) attenuates the inflammatory and fibrotic response that occurs in normal lung tissue after radiation, investigators reported at the 47th annual meeting of the American Society for Therapeutic Radiology and Oncology (abstract 137).

"TGF-β is a very important cytokine that is involved in a number of important processes relevant to both cancer and the treatment of cancer," said Mitchell S. Anscher, MD, professor of radiation oncology, Duke University Medical Center. After radiation therapy, the cytokine stimulates abnormal fibrogenesis, he noted, both promoting deposition of fibrous tissue and inhibiting its degradation. Dr. Anscher and his colleagues tested the investigational anti-TGF-β antibody 1D11 (Genzyme, Cambridge, Mass) in a rat model of radiation-induced lung injury entailing fractionated radiation (40 Gy delivered in 8-Gy fractions on 5 consecutive days to the right hemi-thorax). The antibody or a control antibody was given once only, immediately after the last dose of radiation.

Fischer 344 rats were divided into four groups of 12 animals each: a sham/control group given sham radiation plus a control antibody; a radiation-alone group; a group given radiation plus low- dose 1D11 (0.1 mg/kg) ; and a radiation plus high-dose 1D11 (1 mg/kg) group. Lung tissue was analyzed at 6 weeks and 6 months after radiation.

The anti-TGF-β antibody was well tolerated and had minimal toxicity, Dr. Anscher said. Radiation was associated with increased alveolar wall thickness after 6 weeks, with further and pronounced thickening evident at 6 months. At both time points, the anti-TGF-β antibody attenuated this effect somewhat at the low dose and more so at the high dose.

The antibody also reduced numbers of activated macrophages in lung tissue at both time points after radiation, as assessed by ED-1 immunohistochemical staining. There was again evidence of a dose-response effect, with a roughly 15% reduction in macrophage numbers with the low dose and a roughly 35% reduction at the high dose at 6 months, relative to the radiation-only condition, although numbers were still above those in the sham/controls, he noted.

The percent increase in expression of active TGF-β, relative to the sham/control group, was roughly 100% in the radiation-only group at 6 months, but 55% in the low-dose 1D11 group and 20% in the high-dose 1D11 group. In addition, at the 6-month time point, activation of the TGF-β signal transduction pathway, as assessed by p-SMAD staining, was reduced in each group given anti-TGF-β antibody, relative to the group given only radiation, although again not to the level observed in the sham/control group.

Commenting on the findings, Dr. Anscher said that a single dose of 1D11 seems effective in this model for reducing the severity of lung injury, with an apparent dose response. "It appears that targeting the TGF-β pathway might be a useful approach to the prevention of radiation-induced lung injury," he said.

Lung injury worsened with time even in animals given the antibody, he acknowledged, raising the possibility that the antibody, as administered in the study, may just delay the radiation effects. This finding warrants additional studies with longer durations of administration, Dr. Anscher said.

"Ultimately, we also need to look at some physiologic endpoints, such as breathing frequency, and see whether, even if we can’t completely eliminate all of the fibrotic response, the animals are protected from becoming functionally impaired," he concluded.