US FDA approved therapeutic antibodies with high concentration formulation: Summaries and perspectives

Since 1986 when we first witnessed the approval of monoclonal antibody (mAb) Orthoclone OKT3 by the US FDA, FDA has approved 103 therapeutic antibody drugs in the past 35 years for marketing. Thirty four (34) of these 103 therapeutic antibody drugs (accounting for one third of the total FDA approved antibody therapeutics) are formulated with high protein concentration (100 mg/mL or above). These 34 high concentration antibodies are the focus of this article. The dosage forms of these 34 antibodies are analyzed and discussed in this article. The highest protein concentration of these approved mAbs is 200 mg/mL. The dominant administration route is subcutaneous (76%). Our analysis indicates that it may be rational to implement a platform formulation containing polysorbate, histidine and sucrose to accelerate high concentration formulation development for antibody drugs. The top players/sponsors of high concentration formulation are identified as Roche including its subsidiaries Genentech and Chugai, Novartis, Sanofi, Amgen, GSK, Johnson & Johnson including its subsidiary Janssen, and Regeneron. The FDA approval numbers are significantly increased since 2015 which account for 76% of the total approval number, i.e., 26 out of 34 highly concentrated antibodies. Thus, we believe that the high concentration formulations of antibody drugs will be the future trend of therapeutic antibody formulation development, regardless of the challenges of highly concentrated protein formulations.

AbDiver - A tool to explore the natural antibody landscape to aid therapeutic design

Motivation: Rational design of therapeutic antibodies can be improved by harnessing the natural sequence diversity of these molecules. Our understanding of the diversity of antibodies has recently been greatly facilitated through the deposition of hundreds of millions of human antibody sequences in next-generation sequencing (NGS) repositories. Contrasting a query therapeutic antibody sequence to naturally observed diversity in similar antibody sequences from NGS can provide a mutational road-map for antibody engineers designing biotherapeutics. Because of the sheer scale of the antibody NGS datasets, performing queries across them is computationally challenging. Results: To facilitate harnessing antibody NGS data, we developed AbDiver (http://naturalantibody.com/abdiver), a free portal allowing users to compare their query sequences to those observed in the natural repertoires. AbDiver offers three antibody-specific use-cases: 1) compare a query antibody to positional variability statistics precomputed from multiple independent studies 2) retrieve close full variable sequence matches to a query antibody and 3) retrieve CDR3 or clonotype matches to a query antibody. We applied our system to a set of 742 therapeutic antibodies, demonstrating that for each use-case our system can retrieve relevant results for most sequences. AbDiver facilitates the navigation of vast antibody mutation space for the purpose of rational therapeutic antibody de-sign and engineering. Availability: AbDiver is freely accessible at http://naturalantibody.com/abdiver