Two people were taken out of the plane, according to the California Highway Patrol's traffic log.
The freeway, the main north-south route through southern Orange County, was shut in both directions for about an hour before the northbound side and one southbound lane were reopened.
Orange County Fire Capt. Larry Kurtz said the two people injured were taken to the hospital by a helicopter and their injuries are unknown.
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Drivers stopped to help the people out of the plane.
A small plane sits on the southbound 405 freeway after crash just short of the John Wayne Aiport runway.
A woman who had been on the plane pulled a man from the wreckage and said he was her husband, according to a witness who spoke to KABC. "Essentially tried to get control of my vehicle, checked my passenger to make sure he was OK, gave each other a hug that we were still alive".
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Both occupants of a twin Cessna survived a crash on the 405-freeway shortly after departure from John Wayne Airport.
After an air traffic controller tells the pilot a gear of the plane appears to be up, the pilot says he's trying to gain altitude. The extent of the injuries were not known. It's not clear what caused the plane to crash.
The airport was closed to arrivals, but planes never stopped departing.
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