Geddie, MelissaDenkin, Stevende Rham, Teresse2025-09-1820252025-04-242025de Rham, Teresse. 2025. Specificity and other Biophysical Properties to Guide Developability of Agonistic Bispecific Antibodies. Masters Thesis, Harvard University Division of Continuing Education.31995926https://dash.harvard.edu/handle/1/42719338"Antibody therapeutics have a wide range of applications across many disease areas, including both monoclonal and bispecific molecules. During the initial identification and development of these antibody therapeutics, biophysical properties such as poor stability, low solubility, non-specificity, aggregation, or hydrophobicity can lead to unfavorable development and toxicity profiles. Non-specificity can be an early indicator of poor developability, but has mostly been studied in monoclonal antibodies, not bispecific antibodies. A diverse set of fourteen agonistic bispecific antibodies, composed of six unique binders for BMPRII and five unique binders for ALK1, were selected to be expressed and characterized for their biophysical properties. The agonist bispecific antibodies did not show appreciable increases in non-specificity compared to the parental monoclonal antibodies, although there was an increase in freeze-thaw induced aggregation in bispecific antibodies. These results indicate that the antibody format and biochemical properties of the antibody have a larger influence on overall developability than the mechanism of action of the bispecific antibody."application/pdfenagonismantibodybiophysical propertiesbispecific antibodiesdevlopabilityspecificityBiochemistryImmunologyThesis or Dissertation2025-09-18