Antibody Drug Nomenclature: What is INN a Name? WHO Has Been Changing Them?
In 2014 the World Health Organization (WHO) introduced new definitions for the assignment of antibody international nonproprietary names (INN). A modification of the existing definitions was required because advances in antibody engineering have made classification into the current three main antibody groups (i.e., chimeric, humanized and human) unclear. Unfortunately the new definitions suffer from several major limitations that make them unworkable1. A town hall forum on antibody drug nomenclature was held at the 2015 Antibody Engineering & Therapeutics meeting to update delegates on changes to the INN definitions, discuss their consequences, and solicit input on potential next steps. This session comprised an introductory presentation from Paul Carter based upon a recent publication by 34 authors from 31 different organizations1. The presentation was followed by a panel discussion in which input was solicited from the audience of conference delegates.
The WHO established the INN system in 1950 to provide a unique (generic) name to identify each pharmaceutical substance. This system serves the important function of providing clear identification, and safe prescription and dispensing of medicines to patients. Additionally, the INN system supports communication and exchange of information among health professionals and scientists worldwide. The WHO selects INNs based upon the advice of an expert advisory panel.
The “-mab” stem was introduced in 1990 to indicate monoclonal antibody-based therapeutics. Substems were then developed in 1997 to describe the antibody origin. The most widely used of these species origin substems are: -xi- for chimeric, -zu- for humanized and -u- for human. The origin substems were developed to classify antibodies based upon their “humanness”, and with the assumption that humanness correlates with immunogenicity in patients. Now, nearly 20 years after this system was first introduced, it is appreciated that immunogenicity is a complex multi-factorial problem that is impacted by many parameters beyond amino-acid sequence with no clear sequence-identity threshold for immunogenicity2, 3. Thus, the antibody origin substem may have outlived its original purpose.
New INN definitions for antibodies were undoubtedly needed as the old definitions had become outdated by rapid progress in antibody technologies. These technological changes include additional methods for humanizing antibodies, an increasing diversity of technologies for discovering human antibodies, and the widespread use of engineering to improve the therapeutic potential of antibodies. The creation of a new and robust naming system for antibody drugs is an exceptionally difficult undertaking, especially as technologies for antibody engineering continue to evolve. This challenge is exacerbated by the ever-expanding repertoire of bispecific and multispecific antibodies that are also entering clinical development.
The most recent (2014) WHO definition of chimeric antibodies4 was presented:
“A chimeric antibody is one for which both chain types are chimeric as a result of antibody engineering. A chimeric chain is a chain that contains a foreign variable domain (originating from one species other than human, or synthetic or engineered from any species including human) linked to a constant region of human origin. The variable domain of a chimeric chain has a V region amino acid sequence which, analysed as a whole, is closer to non-human species than to human.”
Similarly, the 2014 WHO definition for humanized antibodies was also described4: “A humanized antibody is one for which both chain types are humanized as a result of antibody engineering. A humanized chain is typically a chain in which the complementarity determining regions (CDR) of the variable domains are foreign (originating from one species other than human, or synthetic) whereas the remainder of the chain is of human origin. Humanization assessment is based on the resulting amino acid sequence, and not on the methodology per se, which allows protocols other than grafting to be used. The variable domain of a humanized chain has a V region amino acid sequence which, analysed as a whole, is closer to human than to other species”
Notably, a definition for human antibodies is missing from the 2014 WHO guidance document on INN4. As for sequence analysis, comparison to human immunoglobulin heavy or light chain germline V-gene segments (IGHV, IGKV or IGLV) should be done with the Immunogenetics Information System® (IMGT®) DomainGapAlign tool (www.imgt.org). This was clarified during an open session of the WHO Expert Group in April 2015. The WHO INN drug names are used worldwide, with the exception of the USA. In the USA, the American Medical Association (AMA) assigns nonproprietary drug names known as United States Adopted Names (USAN). The drug name application processes are separate for WHO-INN5 and AMA-USAN6. However, the WHO and the AMA work in close collaboration; thus, INN and USAN are commonly, but not invariably identical. The AMA has provided USAN/INN requirements for monoclonal antibodies that includes definitions of chimeric, humanized and human antibodies7. These antibody definitions are based upon the sequence identities of their variable regions to human heavy or light chain germline V-gene segments available in the IMGT® reference database: <85% for -ximab with ≥85% being either -zumab or -umab7.
Next, the impact of the new INN rules was considered. Most of the approved humanized antibodies are predicted to be “chimeric” or “mixed” under the new rules. Thus, assignment of INN names using the 2014 definitions is often inconsistent with the previous INN names, as well as with decades of scientific literature. Approved human antibodies are likely to retain their “human” classification under the new INN rules. This has created significant inconsistency among antibodies that are, in fact, similarly “human”, yet which have been assigned different substem names due to the timing of their approval. In addition, some antibodies cloned from human subjects bear many somatic hypermutations (e.g., anti-HIV antibodies) and have < 85% sequence identity with their closest human germline V-gene segments; yet they would fall within the definition of “chimeric”. Thus, it is unclear how antibodies should be classified, as human or humanized, since a ≥85% sequence-identity threshold is being used for both. One justification for this classification is that human antibodies are cloned from human subjects whereas humanized antibodies are engineered, regardless of their origin. However, this is inconsistent with the stated goal of the assessment being based upon a resulting sequence and not the methodology that was used to generate it.
Several of the major limitations of the 2014 INN antibody naming definitions were discussed:
· The definitions do not allow researchers to determine reliably how an antibody will be classified.
· The linking of sequence homology definitions to an evolving database of germline V-gene segments, makes the assignment of the origin substems a moving target.
· It is possible for antibodies to be immunogenic if they are encoded by human germline V-gene sequences that are absent from a given patient’s germline. Thus definitions that rely solely on similarity to germline V-gene sequences may provoke a false impression of their propensity for immunogenicity.
· The definitions are inconsistent with several decades of precedence in naming antibodies in the scientific literature including many previously assigned INN names, i.e., the definitions are incompatible with existing names.
· There is no WHO definition available for what makes an antibody “human” or how a “human” antibody differs from a “humanized” antibody4.
· The sequence-identity threshold of 85% used in the AMA antibody definitions7 to determine human and humanized from chimeric antibodies is arbitrary. –Its relationship to immunogenicity has not been established.
· The antibody J region forms a critical part of all V domains, but is not included in the INN process.
· The extent to which an antibody falls within the definition of human/humanized will be significantly impacted by the identity of the CDRs to the closest human germline V gene segment in the IMGT®
Some options for a new INN antibody system were considered, such as developing new substems (e.g., -sy- for synthetic or -e- for engineered). An alternative option of dropping the origin substem entirely (i.e., use the -mab stem only) was also considered.
The presentation concluded with the message that dialog between the WHO INN Expert Group and key stakeholders is urgently needed to develop a more robust INN system for naming new antibody drugs. The WHO open session with INN stakeholders in April 2016 was identified as an excellent opportunity to initiate such a dialog.
The panel and audience engaged in a lively discussion. In general, participants strongly endorsed the notion that the 2014 antibody INN naming convention has major limitations and urgently needs revision. Audience members recounted a number of examples of nonproprietary names that are illogical in comparison to the prevailing nomenclature. There was very strong support for engaging in a discussion with the WHO to encourage it to address the flaws in the current system. Several participants voiced the opinion that is important that new definitions also govern therapeutic antibody INNs assigned under the 2014 definitions. Several creative suggestions were made for a new naming system. As mentioned, these included dropping the origin substem completely and using only the -mab stem; however, no clear agreement was reached in the time allotted.
1 Jones TD, Carter PJ, Plückthun A, Vásquez M, Holgate RG, Hötzel I, et al. The INNs and outs of antibody nonproprietary names. MAbs 2016; 8:1-9.
2 Baker MP, Reynolds HM, Lumicisi B, Bryson CJ. Immunogenicity of protein therapeutics: The key causes, consequences and challenges. Self/nonself 2010; 1:314-22.
3 WHO-INN: International nonproprietary names (INN) for biological and biotechnological substances (a review) [Internet] 2014.
4 WHO-INN: International nonproprietary names (INN) for biological and biotechnological substances (a review) [Internet] 2014.
5 WHO-INN: Online INN application.
6 AMA-USAN: Online USAN application.
7 AMA-USAN: Monoclonal Antibody Rules.[Internet] Accessed 2015 Oct 2.