When you consider that Harley Quinn first appeared in Batman: The Animated Series as the Joker's chief henchwoman, it seems that the most likely candidate to face Harley in her own movie would be the Dark Knight himself.
While Batman might seem the obvious choice as the antagonist of the Harley
Quinn movie, there are several factors working against it. We already know Batman is showing up in Justice League, and that a Batman solo movie is in the works. Due to us not knowing the specifics of Ben Affleck's contract with Warner Bros., we do not know how many movies he has signed on for. He has already used up at least three of his contractual appearances. If the next few DC movies are financial and critical failures, then he may want to jump ship as soon as possible. Using him in the Harley Quinn film may seem like a waste, when there are so many other potential foes for her to face.
The idea of Batman being the villain in Harley Quinn is not completely out of the realm of possibility. In the slew of bad reviews that followed Batman v Superman and Suicide Squad, two of the most highly regarded performances from those films were Ben Affleck's and Margot Robbie's. Warner Bros. might be so desperate for a hit, that they would put their two most popular characters together.