It sounds as though you might be interested in GULLIVER, a fan-made expansion for GURPS. The original was a hefty tome with a significant amount of material regarding creatures of any scale - from fleas and mice to giants and beyond.
The current edition, for 4e, is a lightweight 2 pages but still addresses issues of size. Specifically regarding your question, it states:
Use relative SM (difference in attacker and target SM) as a bonus on the smaller creature's melee TH and a penalty on the larger crea- ture’s melee TH. Treat hit location TH mods as additional relative SM mods (e.g., a SM 3 Giant's leg [-2 TH] is a SM 1 target). The final net TH mod for SM may not exceed +4.
This is not canon. But the GULLIVER rules are usually well-regarded in the GURPS community.