The World Health Organization (WHO) issues International Nonproprietary Names (INN) for therapeutic antibodies. These INNs contain the suffix -mab preceded by a source (or species) infix such as -xi- for chimeric, -zu- for humanized and -u- for human antibodies. Changes in definitions and procedures, which WHO implemented in 2014, resulted in INN with inconsistent source designations for an array of chimeric and humanized antibodies. Discussions spearheaded by The Antibody Society have now led to a resolution of the issue. At the 64th Consultation on INN held in April 2017, the WHO INN expert group decided to eliminate the source infix. WHO implemented the changes promptly and applicants have already received INN issued under the new naming scheme, i.e., without an INN source infix.
The Antibody Society board members Paul W.H.I. Parren, Paul J. Carter and Andreas Plückthun provide analysis and more information in a Perspective article, Changes to International Non-Proprietary Names for antibody therapeutics 2017 and beyond: Of mice, men and more…, that was published in the August/September 2017 issue of mAbs. The PDF of this article can be downloaded from the mAbs website. As a courtesy to Society members, the PDF of this article is also available here.
Most of the references from the article are available from the links below. To facilitate downloads, the references listed below, with the exception of Ref. 6, 25, 39, 43, have been complied into a single PDF and are available here. Documents cited as Ref. 6, 39 and 43 are available here. Specific documents can be found by searching the PDFs for key words or phrases.
Single documents can be downloaded from the following links:
Ref. 1 is available here.
Ref. 3 is available here.
Ref. 4 is available here.
Ref. 6 is available here.
Ref. 8 is available here.
Ref. 12 is available here.
Ref. 13 is available here.
Ref. 14 is available here.
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Ref. 17 is available here.
Ref. 18 is available here.
Ref. 19 is available here.
Ref. 20 is available here.
Ref. 22 is available here.
Ref. 23 is available here.
Ref. 24 is available here.
Ref. 25 is available here.
Ref. 26 is available here.
Ref. 27 is available here.
Ref. 28 is available here.
Ref. 29 is available here.
Ref. 30 is available here.
Ref. 31 is available here.
Ref. 32 is available here.
Ref. 33 is available here.
Ref. 34 is available here.
Ref. 35 is available here.
Ref. 36 is available here.
Ref. 37 is available here.
Ref. 38 is available here.
Ref. 39 is available here.
Ref. 40 is available here.
Ref. 42 is available here.
Ref. 43 is available here.
Ref. 48 is available here.
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Ref. 60 is available here.
Summary of the Open Session of the 62nd INN Consultation
World Health Organization HQ, Geneva, Switzerland. April 12, 2016.
The official summary is now available
Selected participants:
Meeting Chairperson: Dr. Patience Holland
INN Expert Group chairperson: Dr. Raffaella Balocco-Mattavelli
Antibody Experts of the INN Expert Group:
Dr. Robin Thorpe
Dr. Karin Weisser
Prof. Dr. Menico Rizzi
Prof. Dr. Marie-Paule Le Franc
Participants, The Antibody Society:
Prof. Dr. Andreas Plückthun
Prof. Dr. Paul Parren
The first half of the session was reserved for companies objecting to or requesting specific (small molecule) generic names. This was followed by a number of presentations on biosimilar nomenclature.
The second half of the meeting was reserved for a discussion of the antibody international non-proprietary naming issue. Starting with a presentation by The Antibody Society [1] (Paul Parren), a short Q&A; a presentation by the INN Expert Group [2] (Dr. Robin Thorpe, Prof. Dr. Marie-Paule Le Franc, Prof. Dr. Menico Rizzi and Dr. Karin Weisser); followed by 40 minutes of discussion
Dr. Balocco-Mattavelli opened with saying that they appreciated the initiative of The Antibody Society. The INN committee had therefore decided to change the proceedings of the meeting by also including a presentation by the INN Expert group and thereafter enter into a dialogue.
Dr. Parren’s presentation is here. It was noted that The Antibody Society’s petition is now signed by 297 workers in the field representing 104 academic and commercial institutions from 23 countries, indicating The Antibody Society well represents the Antibody community.
The INN expert group’s presentation is here. Dr. Thorpe summarized the criticism put forward in Jones et al. and noted our petition [2]. With respect to immunogenicity, it was noted that the source designations were never intended, according to Dr. Thorpe, to give information on immunogenicity. Dr. Weisser however indicated that the INN would give “at least some indication” of foreignness, and thus a subdivision should be maintained.
The Jones et al. paper [3] was said to be mistaken in referring to the WHO INN with respect to the 85% homology cut-off. Threshold percentages for sequence homologies have never been published by the INN expert group. Dr. Thorpe noted that implementing the new definitions retrospectively and without notice period indicated the communication could have been better.
Dr. Le Franc described how mAbs are named, also referring to the presentation of The Antibody Society. She stressed and emphasized the importance of the sequence analysis method and examining the sequence as a whole. She noted that the INN expert group does not use a specific sequence cut-off. Dr. Le Franc further explained the IMGT database and use of the DomainGapAlign tool and indicated it is free to use for academic purposes. Commercial use indeed requires a fee that she indicated was 15,000 euros per year, which was argued to be a reasonable expense.
It should be noted that the use of IMGT and DomainGapAlign as well as the required source and top-hit information are indicated in the ‘Request for an INN form and Annex’ [4,5].
Dr. Weisser commented on some of the issues raised in Jones et al., as this paper indicates that it is a flaw to exclude the J region in the alignment. She argued that it is not possible to include the J chain in the comparison, as this would mean the HCDR3 region should be included, which is not feasible. Jones et al. commented on the presence of macaque sequences in the IMGT database. The INN expert group indeed uses the top-hit method, it was explained, but here it is important to note that the antibody will still be considered humanized if there are human antibodies “among the top-hits”. A humanized antibody will be designated as a –zumab, if non-human primate sequences have the highest score as long as there are (lower scoring) human antibody sequences that display sequence similarity in the same range. Therefore, exact cut-offs are not used and some judgment of the examiner is required. It was also emphasized that antibodies isolated from humans will always get a human designation even if they fail the sequence comparison test. The issue of human sequences obtained from transgenic animals and/or libraries was not further discussed. The INN Expert group notes: “INN naming rules for mAbs (Bioreview 2014 [6]) do not contain any percentages as thresholds for the distinction between human/ humanized/ chimeric antibodies. The decision of the INN expert group is based on the results of V region amino acid sequence alignment as a whole (IMGT/DomainGapAlign) and information on the source of the mAb provided by the applicant” [4,5].
Dr. Rizzi pointed out that they thought it is important that sequence comparison is a major tool for the WHO INN to assign antibody categories. He indicated that structural data might be used as additional criteria in the future and that the ‘Annex form’ 5 indicates that structural information in the Protein Data Bank, if available, should be provided. It was not discussed how this information could be used to classify antibodies.
Dr. Thorpe ended with emphasizing that the WHO INN expert group is responsible for selecting the INN in line with current policies. The INN reference for mAb designations is the Bioreview 2014 [ref. 6, see pages 8-11] and homology percentages are not official INN policy.
In the Q&A, Dr. Parren noted that it is appreciated that providing immunogenicity information might not have been the initial intention of the source substem as immunogenicity risk is determined by many factors. However, the INN expert group should be aware that the source substem is generally viewed as providing immunogenicity risk by researchers as well as medical professionals. The main reason for humanizing a sequence is to reduce the immunogenicity risk profile of antibody. The strong perception is that a chimeric antibody is more immunogenic than a humanized or human antibody.
Dr. Plückthun noted that sequence alignments against a database have the strong drawback that the information in the database is variable as sequences are added continuously. The top-matching sequences may therefore come out differently when the analyses are run at different times. This uncertainty is a strong argument against using sequence alignments altogether.
The USAN/FDA observer noted that he was confused as the USAN does use a 90% homology cut-off for human antibodies and a 85% homology cut-off for humanized. He was surprised to hear that the INN expert group and USAN were not aligned and the INN expert group in fact does not support the use of a sequence cut-off. He indicated that at least 50% of mAbs have both an INN and a USAN name. So it should be clarified how this should be handled. (Post-meeting note: It is noted that the sequence homology cut-off has been removed from the USAN application form [7]). Dr. Patrik Mauer from Novartis noted that they have submitted a sequence for which a human antibody was the top-hit, but which was still given a chimeric designation. It was argued that the % homology was too low for a humanized designation. Further clarification of the criteria for giving an INN designation on basis of sequence alignments is therefore needed.
Dr. Balocco-Mattavelli and the Expert group member emphasized that they welcome a further dialogue with The Antibody Society and other stakeholders. It has currently been proposed that a participant from The Antibody Society attends an INN Expert group meeting to further discuss the issue 19-20 September 2016.
Dr. Plückthun and Dr. Parren concluded the meeting with noting that the Antibody Society is very willing to engage in further discussions with the INN expert group to try to resolve the current issues and try to get to a generally acceptable solution.
References:
2. INN Expert Group Presentation by Drs Thorpe, Le-Franc, Rizzi and Weisser at the Open Session of the 62nd INN Consultation. April 12, 2016
3. http://www.tandfonline.com/doi/full/10.1080/19420862.2015.1114320
4. https://extranet.who.int/tools/inn_online_application/INN_online_application_files/INNFORM_072010.pdf (accessed May 19, 2016)
5. https://extranet.who.int/tools/inn_online_application/INN_online_application_files/15_385_Annex_INN_Form.pdf (accessed May 19, 2016)
6. http://www.who.int/medicines/services/inn/BioRev2014.pdf
7. USAN form f.
