Blueprint for antibody biologics developability

ABSTRACT

Large-molecule antibody biologics have revolutionized medicine owing to their superior target specificity, pharmacokinetic and pharmacodynamic properties, safety and toxicity profiles, and amenability to versatile engineering. In this review, we focus on preclinical antibody developability, including its definition, scope, and key activities from hit to lead optimization and selection. This includes generation, computational and in silico approaches, molecular engineering, production, analytical and biophysical characterization, stability and forced degradation studies, and process and formulation assessments. More recently, it is apparent these activities not only affect lead selection and manufacturability, but ultimately correlate with clinical progression and success. Emerging developability workflows and strategies are explored as part of a blueprint for developability success that includes an overview of the four major molecular properties that affect all developability outcomes: 1) conformational, 2) chemical, 3) colloidal, and 4) other interactions. We also examine risk assessment and mitigation strategies that increase the likelihood of success for moving the right candidate into the clinic.

KEYWORDS:

• Antibody
• biologics
• colloidal
• conformational
• developability
• formulation
• manufacturability
• specificity
• stability

Abbreviations

ABlooper – Antibody Looper; Abpred – The Antibody Prediction Database; AC-SINS – Affinity Capture Self-Interaction Nanoparticle Spectroscopy; ADC – Antibody-Drug Conjugate; AEX – Anion Exchange Chromatography; AI – Artificial Intelligence; B₂₂ – Second Virial Coefficient; BvP – Baculovirus Particle; CDR – Complementarity-Determining Region; CEX – Cation Exchange Chromatography; CHO – Chinese Hamster Ovary; CIC – Cross-Interaction Chromatography; CLD – Cell-Line Development; CMC – Chemistry, Manufacturing and Controls; CQA – Critical Quality Attribute; cSDS – Capillary Sodium Dodecyl Sulfate Electrophoresis; DLS – Dynamic Light Scattering; DSC – Differential Scanning Calorimetry; Fab – Fragment of Antigen Binding; Fc – Fragment Crystallizable; FcγRIIIa – Fcγ Receptor IIIa; FcRn – Fragment Crystallizable Neonatal Receptor; GRAS – Generally Regarded As Safe; HC – Heavy Chain; HCP – Host Cell Protein; HIC – Hydrophobic interaction chromatography; HPLC – High Performance Liquid Chromatography; IgG – Immunoglobulin G; IND – Investigational New Drug; kD_iff – Diffusion Interaction Parameter; LC – Light Chain; mAbs – Monoclonal Antibodies; MS – Mass Spectrometry; PD1 - Programmed cell death protein 1; PEG – Polyethylene Glycol; pI – Isoelectric point; PK – Pharmacokinetics; PK/PD – Pharmacokinetic/Pharmacodynamic; ProA – Protein A; PS-20/80 – Polysorbate-20/80; PSR – Polyspecificity Reagent; PTMs – post-translational modifications; R_h – Hydrodynamic Radius; RP – Reverse Phase; SAP – Spatial Aggregation Propensity; ScFv - (Single-Chain Variable Fragment; SEC – Size Exclusion Chromatography; SEC-MALS – Size Exclusion Chromatography with Multi-angle Light Scattering; SPR – Surface Plasmon Resonance; TAP – Therapeutic Antibody Profiler; Tm/Tagg – Temperature of melting and aggregation; TPP – Target Product Profile; UF/DF – Ultrafiltration/Diafiltration; VEGFR2 - Vascular endothelial growth factor receptor 2; V_HH - Variable Heavy-chain Antibody Fragment

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.