I agree with the Carnage reasons, but if you think there's more more emotion or themes to be explored, you're really quite mistaken...
I mean, people have already discussed, in depth, the emotional ramifications of the Lizard scenario for Spider-Man 4...
Spider-Man 5 could have Mysterio, Scorpion, and Black Cat... with the Daily Bugle creating Scorpion as an attempt at superhero to defeat the villain Spider-Man, and he is initially marketed as such, and a good portion of the public buys into it (before he goes completely nuts), Mysterio would obviously be up to his old Mysterio-stuff, and Black Cat would provide a sort of foil to Spider-Man, and additional internal emotional conflict within Peter and the audience, and uncertainty as to whether she is an enemy or an ally... the theme being explored, of course, is that of truth and illusion.
Spider-Man 6 could have the Vulture (or Hobgoblin) and Electro... Electro being an insecure and emotionally unstable man who had a terrible childhood and never really had love, who, upon getting his powers, is manipulated in the direction of evil by Adrian Toomes (for his own personal benefit); as sort of a dark mentor, an evil Uncle Ben to Electro's Peter. We realize that so much of what culminated in Electro becoming a dangerous enemy is the lack of love and guidance from someone like Uncle Ben or Aunt May in his life, and the theme that could be explored is how love and the people around us can impact and shape our lives, and Peter is forced to realize that he is not so different from Maxwell Dillion, who, like himself, was pretty much an ordinary person who has strange powers, and all the baggage that comes with them, thrust upon him without warning or preparation, and, without guidance, love, and support from people like Uncle Ben, Aunt May, Mary Jane and others, he very easily could have gone in the same direction as Electro: the direction of using his powers for destruction. Every man is responsible for his own actions, but we must have the humility to recognize where others have carried us and pushed us in the direction of what's right.
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So...? Too cheesy? Even if those aren't any good, I think they still serve to point out that it is still very possible to pull something of dramatic and emotional value out of the remaining villains.
