Fire crews from Downey, Compton, Santa Fe Springs and Los Angeles County scrambled to put out the blaze as it tore through the block-long abandoned building in the 12800 block of Erickson Avenue.
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AIR7 HD was over the scene around 7 p.m. as intense flames engulfed the building.
The property was once known as the Los Angeles County Poor Farm.
It was built in 1888 to treat patients with mental and chronic illnesses but had fallen into a state of extreme disrepair over the last 30 years.
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No one was injured in the blaze. The cause was not immediately known.