Degradation of surface proteins using bispecific binding agent

The present disclosure relates to, among other things, methods for degrading targeted surface proteins using the ubiquitin pathway by using a bispecific binding agent or an immunoconjugate that binds the targeted surface protein and a membrane-associated ubiquitin E3 ligase. The present disclosure also relates to methods for degrading targeted surface proteins using the ubiquitin pathway using an engineered transmembrane protein that binds the targeted surface protein and exhibits ubiquitin E3 ligase activity. The disclosure also provides compositions and methods useful for producing such bispecific binding agents and engineered transmembrane proteins, immunoconjugates, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating an activity of a cell and/or for the treatment of various diseases such as cancers.