What Spider-Man villains could headline an event? Here an event would be something big enough to take up six issues of a main book, and have some spinoff minis?

In the past, this has been done with Morlun (Spider-Verse), Kraven (Hunted), Harry Osborn (Last Remains), the Jackal (Spider Island, Clone Conspiracy) and Carnage (Absolute Carnage)

So which villains can be the big bad in a story where Spider-Man's going to require a lot of help? And how would it go?