The INNs and outs of antibody nonproprietary names

Abstract

An important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a -mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies.

Keywords: Complementarity Determining Region (CDR); International Immunogenetics Information System (IMGT); International Nonproprietary Name (INN); World Health Organization (WHO); antibody; chimeric; definition; framework; humanized; monoclonal.

Figure 1.

BLAST ⁸ identity analysis of (a) pertuzumab VH chain and (b) palivizumab VH chain. The humanized sequences are compared to their closest human germline counterparts (both GenBank accession numbers and IMGT® identifiers are shown). Identity, indicated by dots, and sequence differences are shown below the humanized antibody sequences. IMGT® numbering and CDR definitions (boxed) ⁷ are used with sequence gaps indicated by dashes.

Figure 2.

(a) BLAST ⁸ comparison of murine IGHV5-6*01 framework 2 with human IGHV3-30*01 framework 2. (b) Stereo view of an overlay of framework 2 from 3FFD (dark grey) with framework 2 of 2ADG (light grey). Only back-bone atoms are shown with the exception of lysine 48. The location of glycine/arginine 49 is indicated. The structures were analysed using Swiss-PDB Viewer ⁴⁷ (http://www.expasy.org/spdbv/).