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Set a few months after the events of the film, Peter Parker and Gwen Stacy sneak into the restricted areas of Oscorp after hours, where Gwen reveals her suspicions that they may be continuing the cross-species experiments of Dr. Curt Connors, who had become the monstrous Lizard. They are caught by Alistair Smythe, the new Oscorp director, who confirms Gwen's suspicions, although the cross-species carry a powerful virus and are to be disposed.

However, the cross-species all react to the presence of Peter, a cross-species himself, and break out, infecting all of the scientists, including Smythe and Gwen, in the process. Smythe unleashes his security robots, which are programmed to defend them from cross-species. Peter quickly dons his Spider-Man suit and gets the infected to quarantine, fighting off the robots and destroying the S-01 in the process, but is unable to stop the cross-species and the virus from escaping into the city.