Biophysical properties of the clinical-stage antibody landscape.


Abstract

Antibodies are a highly successful class of biological drugs, with over 50 such molecules approved for therapeutic use and hundreds more currently in clinical development. Improvements in technology for the discovery and optimization of high-potency antibodies have greatly increased the chances for finding binding molecules with desired biological properties; however, achieving drug-like properties at the same time is an additional requirement that is receiving increased attention. In this work, we attempt to quantify the historical limits of acceptability for multiple biophysical metrics of "developability." Amino acid sequences from 137 antibodies in advanced clinical stages, including 48 approved for therapeutic use, were collected and used to construct isotype-matched IgG1 antibodies, which were then expressed in mammalian cells. The resulting material for each source antibody was evaluated in a dozen biophysical property assays. The distributions of the observed metrics are used to empirically define boundaries of drug-like behavior that can represent practical guidelines for future antibody drug candidates.

Submission Details

ID: pkTmYXW43

Submitter: Stephanie Contreras

Submission Date: Dec. 11, 2019, 2:51 p.m.

Version: 1

Publication Details
Jain T;Sun T;Durand S;Hall A;Houston NR;Nett JH;Sharkey B;Bobrowicz B;Caffry I;Yu Y;Cao Y;Lynaugh H;Brown M;Baruah H;Gray LT;Krauland EM;Xu Y;Vásquez M;Wittrup KD,Proc Natl Acad Sci U S A (2017) Biophysical properties of the clinical-stage antibody landscape. PMID:28096333
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
4HAG 2012-09-26T00:00:00+0000 3.4 Crystal structure of fc-fragment of human IgG2 antibody (centered crystal form)
4HAF 2012-09-26T00:00:00+0000 2.04 Crystal structure of fc-fragment of human IgG2 antibody (primitive crystal form)
4L4J 2013-06-07T00:00:00+0000 1.92 Crystal structure of fc-fragment of human IgG2-Sigma antibody
3EO1 2008-09-26T00:00:00+0000 3.1 Structure of the Fab Fragment of GC-1008 in Complex with Transforming Growth Factor-Beta 3
5LG1 2016-07-05T00:00:00+0000 2.7 Room temperature structure of human IgG4-Fc from crystals analysed in situ
4D2N 2014-05-12T00:00:00+0000 2.7 Crystal structure of deglycosylated serum-derived human IgG4 Fc
1ADQ 1997-02-18T00:00:00+0000 3.15 CRYSTAL STRUCTURE OF A HUMAN IGM RHEUMATOID FACTOR FAB IN COMPLEX WITH ITS AUTOANTIGEN IGG FC
4C54 2013-09-10T00:00:00+0000 1.9 Crystal structure of recombinant human IgG4 Fc
5W5N 2017-06-15T00:00:00+0000 1.85 Crystal structure of human IgG4-Sigma2 Fc fragment
5W5M 2017-06-15T00:00:00+0000 1.9 Crystal structure of human IgG4-Sigma1 Fc fragment

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
94.7 Immunoglobulin kappa light chain P01602 KV105_HUMAN
100.0 Immunoglobulin kappa light chain P01834 IGKC_HUMAN
100.0 Immunoglobulin kappa light chain P0DOX7 IGK_HUMAN
90.9 Immunoglobulin gamma-1 heavy chain P01861 IGHG4_HUMAN
90.9 Immunoglobulin gamma-1 heavy chain P01859 IGHG2_HUMAN
100.0 Immunoglobulin gamma-1 heavy chain P01857 IGHG1_HUMAN
100.0 Immunoglobulin gamma-1 heavy chain P0DOX5 IGG1_HUMAN