Provided are novel fully human monoclonal antibodies that bind to human 4-1BB. It also provides the methods of hybridoma generation using humanized rats, the nucleic acid molecules encoding the anti-4-1BB antibodies, vectors and host cells used for the expression of anti-4-1BB antibodies. The invention further provides methods for validating the function of antibodies in vitro and the efficacy of antibodies in vivo. The antibodies of invention provide a very potent agent for the treatment of multiple cancers via modulating human immune function.