Antibody-derived novel modalities have become a significant portion of the early-stage R&D pipeline in bio-pharmaceutical companies. Understanding the in vivo stability and degradation propensity of these new molecular entities is both critical and challenging. Due to the complexity of in vivo sample matrices such as serum, plasma and tissue homogenate, affinity capture enrichment is often applied prior to LC-MS intact analysis for the characterization of the stability profile of novel modalities. This approach has been informative but encountered sensitivity as well as quantitation challenges when analyzing drug candidates significantly larger than antibodies (e.g. multivalent antibodies with a molecular weight well over 200 kDa). Here we report a holistic approach to characterize and quantitate the in vivo degradation products of novel modalities using the combination of intact LC-MS and highly sensitive and robust CE workflows. The improved sensitivity and the simplified quantitative workflow of CE-based methods provide complementary information to LC-MS intact analysis, and enables a faster and more reliable data turnaround to trigger indepth investigation and to gate or rank drug candidates.