Characterization of complex biotherapeutics to assess susceptibilities and product quality attributes is routinely performed during biopharmaceutical product development, but characterization of material from serum offers a physiological perspective and may predict drug performance in vivo. In this work, a non-covalent antibody-small molecule (mAb-NCE) complex from rat serum was screened for stability using LC-MS approaches. Quality attribute monitoring of immunocaptured antibody was performed for tryptic peptides containing Met, Asn, Asp or Lys residues from the CDR/variable regions for oxidation, deamidation, isomerization and glycation quantitation, respectively. In addition, a native protein MS method was developed to characterize intact mAb-NCE complex from serum. LC-MS data enabled ex vivo stability assessment of sequence-related modifications and may be applied to determine stoichiometric ratio of mAb/ligand.