Lopsided, aka severely disadvantaged, match-ups exist when characters with a huge weakness in one area play against character with that as a huge strength. Example: Nu-13 is not a strong character with tools for everything, but she destroys Tager because his main weakness is her main strength and Lambda 5D eats spark bolt. For well-rounded characters, their strength is that they have no weakness. This only creates lopsided match-ups when all of their tools are too strong (CP1.0 Koko).
EDIT: For the record, I'm assuming that lopsided = worse than 6-4.