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.

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration

“…32 Under the 2014 INN/WHO method for assigning generic names, rozanolixizumab was given the -xizu- sub-stem, designating it a chimeric/humanized molecule; the chimeric designation was assigned due to sequence similarities with Macaque monkey IgG sequences, however, no Macaque monkey sequences were used in the humanization process. This designation has been criticized and used as an example in the literature to show some of the inaccuracies and inconsistencies with the INN/WHO system; 33,34 the naming system has subsequently been revised and superseded. 34 …”

Multivariate Analysis of Two-Dimensional 1H, 13C Methyl NMR Spectra of Monoclonal Antibody Therapeutics To Facilitate Assessment of Higher Order Structure

“…12 Indeed a number of 1D 1 H NMR based methods have been recently proposed for chemometric HOS analysis of mAbs. 3,4,13–15 The application of chemometric approaches to the problem of 2D spectral analysis of protein therapeutics is less well-established, but is actively being explored. Proposed approaches include direct point-to-point linear correlation analysis of the processed data matrix, 16 spectral covariance analysis, 17 multivariate principal component analysis on both the processed data matrix, 18,19 as well as on tables of peak positions and intensities, 5 spectral distance metrics such as nearest neighbor approaches on peak tables, 20 and total spectral Euclidian deviation.…”

Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples

“…The resulting percentage of human residues in Vk, identified by IMGT/ DomainGapAlign, is 90.5»92.3%, which is comparable to approved fully human antibodies and qualifies the name "-umab" according to the current World Health Organization (WHO) International Nonproprietary Name (INN) definitions; whereas the percentage of human residues in VH is 77.8»83.8%, which is similar to the currently approved humanized antibodies (-zumab), but is less than 85% and could also fall into the "chimeric" category (-ximab). 38 To further reduce the immunogenicity, one can consider removing T-cell epitopes 8,39,40 from the grafted combined Kabat/IMGT/Paratome CDRs, where it is the major immunogenic site that we have seen in humanized murine antibodies. 8 Anti-mesothelin immunotoxins have been developed for clinical trials.…”