Abstract
Multiple therapeutic proteins can be combined into a single dose for synergistic targeting to multiple sites of action. Such proteins would be mixed in dose-specific ratios to provide the correct potency for each component, and yet the formulations must also preserve their activity and keep degradation to a minimum. Mixing different therapeutic proteins could adversely affect their stability, and reduce the shelf life of each individual component, making the control of such products very challenging. In this study, a therapeutic monoclonal antibody and a related Fab fragment, were combined to investigate the impact of coformulation on their degradation kinetics. Under mildly destabilizing conditions, these proteins were found to protect each other from degradation. The protective effect appeared to originate from the interaction of Fab and IgG1 in small soluble oligomers, or through the rapid coalescence of pre-existing monomeric IgG1 nuclei into a dead-end aggregate, rather than through macromolecular crowding or diffusion-limitations.
Highlights
Multiple therapeutic proteins can be combined into a single dose for synergistic targeting to multiple sites of action
The combination of nivolumab (Opdivo, anti-PD-1 antibody) and ipilimumab (Yvery, anti-CTLA-4 antibody), for example, inhibits two immuno-oncology checkpoints that shows encouraging response and survival rates in melanoma patients compared to the nivolumab single t herapy[7,8]
We investigated whether the Fab stabilized the IgG1 via a hard-shell macromolecular crowding effect
Summary
Multiple therapeutic proteins can be combined into a single dose for synergistic targeting to multiple sites of action. Monoclonal antibodies (mAb) are a leading class of pharmaceutical products with over 80 approved products, and more than 570 products entering different stages of clinical trials as of 2 0191 Among these products, most antibodies are formulated and administrated as individual therapeutic agents. There are a significant number of active clinical trials for combinations of other mAb products, typically involving 2–6 mAbs[9,10,11], and in some cases up to 2512 As such clinical trials are beginning to reveal synergistic effects between multiple antibodies, this approach is becoming increasingly popular[3,13]. We used a 144 kDa full-size monoclonal antibody (IgG1) and a 47 kDa antigen-binding fragment Fab as a model system to study the degradation of therapeutic proteins in coformulation. IgG1 was characterized separately as a reference system for the degradation
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