To me the issue with getting bigger is how many massive planes are really needed in the marketplace for hub/hub movements. You have to sell so many aircraft to recoup the tooling and design costs. A good example is Concorde where operationally it made some sense but the marketplace was never large enough for the manufacturer to turn a profit. The A380 seems to be going the same direction (time will tell).
If you look at JFK<->UK and the number of flights there is no doubt that reducing to a couple A380's JFK<->LHR would be a lot cheaper as you would need less crew, ground, maintenance, etc. on the smaller fleet. The consumer though seems to prefer a lot more time slots and more point/point versus hub. Given the choice of flying 7hrs to LHR and then sitting around a couple of hours and connecting to MAN, I would prefer to pay more for a direct flight.