Stable High‐Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient

Abstract

Monoclonal antibodies (mAbs) are a staple in modern pharmacotherapy. Unfortunately, these biopharmaceuticals are limited by their tendency to aggregate in formulation, resulting in poor stability and often requiring low concentration drug formulations. Existing excipients designed to stabilize formulations are often limited by their toxicity and tendency to form particles such as micelles. Here, the ability of a simple "drop-in," amphiphilic copolymer excipient to enhance the stability of high concentration formulations of clinically relevant mAbs without altering their pharmacokinetics or injectability is demonstrated. Through interfacial rheology and surface tension measurements, it is demonstrated that the copolymer excipient competitively adsorbs to formulation interfaces. Further, through determination of monomeric composition and retained bioactivity after stressed aging, it is shown that this excipient confers a significant stability benefit to high concentration antibody formulations. Finally, it is demonstrated that the excipient behaves as an inactive ingredient, having no significant impact on the pharmacokinetic profile of a clinically relevant antibody in mice. This amphiphilic copolymer excipient demonstrates promise as an additive to create stable, high concentration antibody formulations, thereby enabling improved treatment options such as a route-of-administration switch from low concentration intravenous (IV) to high concentration subcutaneous (SC) delivery while reducing dependence on the cold chain.

Defining Structure-Function Relationships of Amphiphilic Excipients Enables Rational Design of Ultra-Stable Biopharmaceuticals

“…Recently, we validated that the high-throughput combinatorial synthesis of amphiphilic copolymers could yield diverse libraries of surfactant excipients, enabling identification and optimization to dramatically improve the stability of biopharmaceuticals, including insulin and antibodies. 4,5,12,13 The use of controlled radical polymerization techniques allowed for the facile combination of 11 chemically distinct monomers into 90 unique copolymers with a constant degree of polymerization. By screening this library with insulin stability assays, a specific polymer composition was isolated that acted as a potent biopharmaceutical excipient, improving formulation stability over 50-fold compared to commercial surfactant excipients.…”

Development and biophysical characterization of a humanized FSH–blocking monoclonal antibody therapeutic formulated at an ultra-high concentration

“…However, ultra-high concentration monoclonal antibody formulations are associated with physical and chemical instabilities depending on the physicochemical properties of the specific monoclonal antibody ( Bramham et al, 2021 ; Jiskoot et al, 2022 ; Klich et al, 2023 ). Notably, due to the higher concentrations, these formulations may be very viscous or gelatinous, leading to increased tissue back pressure and pain at the injection site ( Whitaker et al, 2017 ; Jezek et al, 2011 ).…”

Sequentially Controlled Recognition of Different Proteins Using Programmable Protein Imprinted Nanospheres

“…[5] However, these natural macromolecules always suffer from the high cost, difficulty in preparation, and poor stability during the real application. [6] Therefore, it is of great importance to develop artificial materials for precise protein recognition. Protein imprinted materials are specific protein recognition materials developed DOI: 10.1002/smll.202304957 under the inspiration of the specific recognition principle of antibodies and lectins.…”