Clustering: a rational design principle for potentiated antibody therapeutics

Oostindie, S.C. (2022)

Doctoral Thesis

Antibodies, the cardinal effector molecules of the immune system, are being leveraged to enormous success as biotherapeutic drugs. Adaptive immune responses consist of epitope-diverse polyclonal antibody mixtures that are capable of neutralizing their targets via binding interference and by mediating humoral and cellular effector functions. A mechanistic theme fundamental to virtually all aspects of antibody biology, including antibody-antigen binding, clonal selection and effector functions, is the utilization of avidity to drive and tune functional responses. Manipulating antibody avidity has since emerged as an important design principle for enhancing or engineering novel properties in antibody biotherapeutics. In the context of ‘classical’ effector functions, complement-dependent cytotoxicity (CDC) can be improved by single point mutations in the IgG Fc domain that increase intermolecular Fc-Fc interactions upon binding to membrane-bound targets, thereby facilitating enhanced IgG hexamer formation and C1q binding. Such engineering approaches illustrate the relevance of promoting avidity interactions such as antibody clustering to enhance effector functions. The aim of this thesis was to explore the role of antibody avidity interactions, and more specifically the importance of ‘ordered clustering’, in antibody mechanisms of action and to apply the knowledge obtained in designing novel and improved antibody-based therapeutics

• Antibody therapy
• Molecular engineering
• Drug discovery
• Avidity
• Complement cascade
• B-cell lymphoma
• Leukemia
• Hematological malignancies
• Immunotherapy
• Cancer immunotherapy

• All authors: Oostindie, S.C.
• Supervisor: Parren, P.W.H.I.
• Co-supervisor: Breij, E.C.W.
• Committee: Borst, J.G.; Huizinga, T.W.J.; Trouw, L.A.; Spriel, A.B. van; Vidarsson, G.
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2022-05-18
• ISBN (print): 9789464215724
• Sponsorship: Genmab