Avastin injections on the corneal rejection landscape

High-risk transplants get a potential boost

The hope is that Avastin can help stave off rejection such as the kind seen here in this vascularized high-risk transplant Source: Reza Dana, M.D.

Use of subconjunctival Avastin (bevacizumab, Genentech, South San Francisco, Calif.) helped reduce graft rejection in high-risk corneal transplantation cases in a mouse model, according to Reza Dana, M.D., Claes H. Dohlman professor of ophthalmology, and chief, Cornea Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston. Such transplants are among the most common kind performed worldwide, including in the U.S. where numbers range between 35,000 and 40,000, Dr. Dana said.
“When it comes to transplant failure the major concern is rejection. Rejection is the main reason for graft failure, and neovascularization is a predictable risk factor for rejection,” Dr. Dana said. “Neovascularization is mediated by the VEGF [vascular endothelial growth factor] molecule and Avastin is one of the antibodies against VEGF.” With this in mind investigators decided to take a look at Avastin’s effect on transplant survival.

Weighing different approaches

They considered both topical and subconjunctival use of this anti-VEGF antibody in a mouse model of high-risk transplants. “The reason that we elected to look at both topical and subconjunctival (Avastin use) is that when we give a subconjunctival injection there is a depot effect—the medication is retained at the site for much longer than when it’s given topically,” Dr. Dana said.
For the study, published in the November 2009 issue of Investigative Ophthalmology and Visual Science, the mice were divided into three treatment groups. In one group patients received topical 2.5% bevacizumab three times a day for 3 weeks. In a second group 0.5 mg of bevacizumab was injected subconjunctivally following transplantation on days 0, 4, 8, and 15. In the control group no treatment was given. Investigators examined grafts twice a week by slitlamp and digitally photographed these once a week to score for opacity.
Results were promising, particularly for the subconjunctival approach. “We saw a modest increase in survival in using the drop, but it wasn’t statistically significant, Dr. Dana said. “However, it was very significant when we used a subconjunctival treatment.” Investigators found that neovascularization and vessel caliber were reduced by both topical and subconjunctival Avastin treatment. However, with the subconjunctival approach there was much more significant regression of the corneal neovascularization. In this group at week eight there was a mean reduction in neovascular area of 55% compared with just 33% in the topical group. In addition, when it came to new areas of blood vessel invasion, only the subconjunctival approach resulted in a significant reduction. From a practical standpoint the subconjunctival approach was the only one that had a significant effect on graft rejection. “We saw a modest increase in survival when using the drop but it wasn’t statistically significant. It was very significant when we used a subconjunctival treatment,” Dr. Dana said. In this particular model of the high-risk transplant, 100% of the grafts were rejected in the second week in the control group. Mice who received topical Avastin treatment fared a bit better than controls. “In the topical treatment group we still lost all the transplants but at a later time point, and the overall rate of rejection did not change,” Dr. Dana said. “When we gave the subconjunctival injection we got indefinite survival of about 33%.”
Dr. Dana sees this number as conservative since investigators were using a humanized antibody in a mouse model. “We predict that an anti-VEGF strategy will be even more effective in a human setting as long as we’re using a humanized antibody,” he said.

Promoting transplant survival

“The take-home message is that a blockade of VEGF can be a novel strategy for promoting survival of high-risk transplants,” Dr. Dana said. “It’s a very important message because given our current pharmaceutical armamentarium, the vast majority of high-risk transplants reject immediately, even if we put the patients on local or systemic immune suppression.” He sees the idea of being able to suppress blood vessel growth and promote transplant survival as very important. “The fact that we’re able to show this by not systemically treating the animal is particularly important because our previous work has shown that we can block VEGF and promote transplant survival, but that requires a systemic injection,” Dr. Dana said. “For the first time we showed that local use is effective.”
Dr. Dana was pleased with the outcomes. “I was gratified to see that our hypothesis held true simply because it is so difficult to use any strategy that appreciably affects the rate of rejection of these high-risk transplants,” he said.
Going forward, Dr. Dana hopes to soon try this in practice. “We intend to pursue this,” he said. “We have received IRB [institutional review board] approval in our institution at Massachusetts Eye and Ear for beginning to evaluate the use of Avastin in a transplant patient at the time of surgery.”

Editors’ note: Dr. Dana has no financial interests related to his comments.

Contact information

Dana: 617-573-4331, Reza_Dana@meei.harvard.edu