Your question is posted in a forum for Class A, B, C rigs. So, you are going to get answers that lean towards the positives of the E350 E450 chassis.
If you posted this same question on a Class A forum, you would get positives all about the F53.
Ignoring the available storage and living space differences, and just focusing on handling characteristics......
I have owned both. Yes, Class A, B, and Cs handle more like the van chassis they are made from. Their smaller size and lower center of gravity means less roll and pitch as you amble down the road.
However, a nicely appointed modern Class A with "all the fixins" such as a rear track bar, sway bars, nice shocks, and a centering stabilizer system will feel very nice and comfortable during long trips also, (and you have MUCH more of everything).
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