Antitransforming Growth Factor-beta Antibody 1D11 Ameliorates Normal Tissue Damage Caused by High-dose Radiation

Purpose: The aim of this study was to determine whether a neutralizing transforming growth factor-beta (TGFbeta) antibody can prevent radiation (RT) induced lung injury.

Methods And Materials: Fractionated and sham right lung irradiation in Fischer 344 rats was delivered to assess the radioprotective effect of the antibodies. Animals were divided into the following groups: (1) control (sham RT, control antibody 13C4); (2) RT (800cGy x 5)+13C4); (3) RT + 0.1 mg/kg 1D11 anti-TGFbeta antibody; and (4) RT + 1 mg/kg 1D11 antibody. Antibodies were intraperitoneally administered immediately after the last fraction of RT. Animals were sacrificed at 6 and 26 weeks after irradiation. Lungs were assessed for histologic changes, activation of macrophages, expression/activation of TGFbeta and its signal transduction pathway.

Results: At 6 weeks post-RT, there was a significant reduction in macrophage accumulation (p = 0.041), alveolar wall thickness (p = 0.0003), and TGF-beta activation (p = 0.032) in animals receiving 1.0 mg/kg 1D11 vs. in the control group. However, at 6 weeks, the low dose of 1D11 antibody (0.1 mg/kg) failed to produce any significant changes. At 6 months post-RT, radioprotection is apparent for the group receiving 1.0 mg/kg 1D11, with activated macrophages (p = 0.037), alveolar wall thickness (p = 0.0002), TGFbeta activation (p = 0.002) and its signal transduction proteins (p < 0.05) compared with the control group.

Conclusions: Administration of a single dose of 1.0 mg/kg of the anti-TGFbeta antibody 1D11 resulted in decreased morphologic changes, inflammatory response, and reduced expression and activation of TGFbeta 6 weeks and 6 months after 40 Gy to the right hemithorax. Targeting the TGFbeta pathway may be a useful strategy to prevent radiation-induced lung injury.