What are the updated recommendations for naming monoclonal antibodies?

Introduction

In 1986, the United States (US) Food and Drug Administration (FDA) approved the first monoclonal antibody product, muromonab-CD3, a monoclonal mouse immunoglobulin agent to prevent rejection after renal transplantation.¹ Although muromonab-CD3 is no longer being manufactured, a number of advances have been made since its approval, leading to rapid expansion of the monoclonal antibody market.² In 2015, 50 monoclonal antibodies were FDA-approved; as of April 2021, the number of approved monoclonal antibodies doubled to 100 with agents covering a wide range of therapeutic areas.³ Recommendations for nonproprietary (generic) naming of monoclonal antibodies come from the International Nonproprietary Name (INN) working group of the World Health Organization and the United States Adopted Name (USAN) Council.⁴ Historically, nearly all monoclonal antibodies have been named with the suffix -mab; however, there are currently over 800 names selected in the monoclonal antibody category.⁵ This rapid expansion, along with use of a single suffix, increases the likelihood that 2 monoclonal antibodies could be named with look-alike, sound-alike names; thus, the INN and USAN have updated their recommendations for naming of monoclonal antibodies as of December 2021.⁶ The purpose of this FAQ is to review the development of monoclonal antibodies over time, describe how they are named, and discuss updates from the INN and USAN that will modify how monoclonal antibodies are named going forward.

Monoclonal Antibody Development Over Time

The initial rodent (murine) monoclonal antibodies were associated with high levels of immunogenicity (development of anti-mouse antibodies by the human administered the drug), which resulted in reduced efficacy and the potential for severe infusion reactions.⁷ In an attempt to allay this issue, future monoclonal antibodies were developed using genetic engineering to replace murine variable domain sections of the immune globulin chains with human constant region domains, thus leading to the development of chimeric monoclonal antibodies.⁸ Abciximab was the first chimeric monoclonal antibody to be approved by the FDA in 1994. However, chimeric antibodies continued to have significant issues with immunogenicity. Upon further research, a complementary-determining region (CDR) grafting technique was developed. This technique allowed for creation of humanized monoclonal antibodies via grafting of CDRs from the variable domains of murine antibodies onto human variable domains. Daclizumab was the first humanized monoclonal antibody to reach the market in 1997, ushering in a new era of drug therapy for diseases requiring long-term therapy. In 1990, a researcher identified an initial technique for creation of fully human monoclonal antibodies using phage display; since then, additional techniques have also been developed including use of transgenic mice and derivation of recombinant antibodies from a single B cell. Adalimumab, a tumor necrosis factor α inhibitor, was the first fully human monoclonal antibody, approved by the FDA in 2002 for the treatment of rheumatoid arthritis.

Components of Monoclonal Antibody Nomenclature

Initial INN Naming Convention

In 1995, the INN published the first guidance document on naming of pharmaceutical agents to allow for international recognition of drug products based on their nonproprietary name.⁹ For monoclonal antibodies, this initial guidance recommended that each agent have a random prefix chosen by the manufacturer to allow for a distinctive name and to enhance the sound of the drug’s name, a general stem (suffix) of ‑mab for all products, and infixes (previously referred to as substems) to indicate the source (human or animal), disease or target of the drug, and specific types of tumors, as applicable (see Table 1).  Prior to 2017, all monoclonal antibodies were named by combining the following, in sequential order: prefix, drug target (infix A), source/species (infix B), and suffix (-mab).¹⁰ One example of an INN provided in the 1995 update is altumomab; this name combines the prefix (al-), infix referring to a miscellaneous tumor target (-tum-), mouse species (-o-) and the suffix (-mab).⁹

Updates to INN Naming Recommendations Over Time

After the initial publication in 1995, the INN has published several updates to their nomenclature recommendations; many updates coincided with research developments, including additional infixes for new targets (eg, fungal [-f(u)-], interleukin [k(i)-], bone [-s(o)-]) and sources (eg, chimeric-humanized, humanized).¹⁰ In 2017, the INN nomenclature recommendations for monoclonal antibodies were updated to remove the species from the name.¹¹ This action was taken for 2 reasons: 1) an influx of applications for naming of new monoclonal antibodies, and 2) a concern that companies were using the species as a marketing tool due to an unfounded perception that certain species infixes implied reduced immunogenicity compared to others. An example of a drug named after this change is bamlanivimab, a treatment for COVID-19; its name contains a prefix (bamlani-), infix (-vi-; referring to the drugs design to target a virus), and suffix (-mab).¹²

United States Adopted Names Council

The US does not directly follow INN recommendations for naming of drugs; rather, the USAN Council meets biannually to assign nonproprietary drug names in the US.^4,13 The USAN Council includes representation from the FDA, American Medical Association, United States Pharmacopeia, and American Pharmacists Association; the Council also includes one member-at-large.¹³ The USAN Council and INN program work closely together to maintain consistency of nonproprietary drug names both within and outside of the US.⁴ Thus, USAN follows the same naming convention as INN and nonproprietary product names given by INN and USAN are usually the same, with a few rare exceptions (eg, acetaminophen in the US versus paracetamol internationally). A product manufacturer typically initiates the process to obtain a nonproprietary name (from INN or USAN) early on in clinical development; these submissions often occur when a pharmaceutical agent is in phase 1 or 2 clinical trials.

December 2021 Updates to the INN and USAN Nomenclature Recommendations

As mentioned previously, the INN and USAN recommendations for naming monoclonal antibodies were updated in December 2021 to mitigate confusion as many new monoclonal antibody drugs are in various stages of the approval process.^5,14 These updates are in effect as of January 2022, and will apply only to newly named drugs; preexisting names will not be revised to follow the new naming convention.⁵ The main update made was to remove the longstanding -mab suffix and replace it with 4 potential alternative suffixes that further divide the monoclonal antibodies that contain an immunoglobulin variable domain. Each new suffix is described in the subsequent sections.

Group 1: -tug

The first group will contain the suffix -tug, which refers to unmodified immunoglobulins.^5,14 These monoclonal antibodies are monospecific, meaning that they target a single antigen. Group 1 includes full-length immunoglobulins and immunoglobulins with unmodified fragment crystallizable (Fc) regions. Both INN and USAN include the following examples that would qualify as unmodified immunoglobulins: IgA, IgD, IgE, IgG, IgM, only allelic variants, glycoengineering that does not involve mutation, and a C-terminal lysine deletion that does not involve another mutation in the Fc region.

Group 2: -bart

The suffix naming for Group 2 (-bart) comes from antibody artificial.¹⁴ Monoclonal antibodies in group 2 are also monospecific, but unlike Group 1 agents, they either have engineered constant domains or contain a point mutation elsewhere that was introduced artificially by engineering.^5,14 For example, engineering of the Fc region of an antibody can be used to modify sugars and amino acid residues to alter receptor binding affinity.¹⁵ Atezolizumab is an example of a monoclonal antibody currently on the market that is artificially engineered.¹⁶ Atezolizumab is engineered in development to mutate the Fc region to reduce antibody-dependent cell-mediated and complement-dependent cytotoxicity.

Group 3: -mig

Group 3 agents will end with the suffix -mig and contain multi-immunoglobulins (bi- or multi-specific agents that target more than 1 antigen) with any structure.^5,14 Bi- or multi-specific monoclonal antibodies are created by linking 2 antigen binding domains using protein engineering.⁸ This allows a single antibody to bind to 2 or more antigens at once. One example of a bi-specific monoclonal antibody that is current on the market is blinatumomab.^8,17 The drug, which is a treatment for B-cell precursor acute lymphoblastic leukemia, is a bispecific T-cell engager. It works by binding to cells that contain the CD19 antigen and to the CD3ε signaling chain of the T-cell receptor complex. The drug must bind to both targets to exert its pharmacologic effects.

Group 4: -ment

The final new suffix group, -ment, contains fragments- monospecific agents that contain a fragment derived from the variable domain of an immunoglobulin.^5,14 An example of a currently approved immunoglobulin fragment is Digifab, which is prepared by injecting sheep with a digoxin analogue, collecting the serum, and then purifying the antigen-binding fragment (Fab) portion of an IgG antibody against digoxin.¹⁸

Although the new suffixes are the most significant change to the INN and USAN recommendations, the monoclonal antibody naming recommendations have also been updated to include new infixes to better define the action or specific target of newly developed monoclonal antibodies.⁵ As was noted previously, product manufacturers often file for nonproprietary drug names very early on in clinical development; infixes are assigned based on the proposed mechanism of action of a drug product at the time the name request is filed.¹⁴ The INN acknowledges that mechanisms of action for monoclonal antibodies are complicated, may vary by indication, and may not be fully elucidated at the time of submission for a name request. Table 2 below provides a current list of all of the infixes described in the 2021 update.^5,14

Conclusion

The monoclonal antibody market is rapidly expanding, with the number of approved monoclonal antibodies doubling over the past 6 years. Conventional naming of these agents, as recommended by the INN and USAN, recommended a suffix of -mab for all monoclonal antibodies. Given the recent influx of monoclonal antibodies in various stages of clinical development, INN and USAN recommendations were recently updated to incorporate 4 new suffixes going forward. As agents begin to be approved under this new naming scheme, it will be important for clinicians to be able to understand and recognize these differences.

References

1. Liu JK. The history of monoclonal antibody development – progress, remaining challenges and future innovations. Ann Med Surg (Lond). 2014;3(4):113-116. doi: 10.1016/j.amsu.2014.09.001
2. Reichert JM. Marketed therapeutic antibodies compendium. MAbs. 2012;4(3):413-415. doi: 10.4161/mabs.19931
3. Mullard A. FDA approves 100th monoclonal antibody product. Nat Rev Drug Discov. 2021;20(7):491-495. doi: 10.1038/d41573-021-00079-7
4. United States Adopted Names: monoclonal antibodies. American Medical Association. Accessed January 25, 2022. https://www.ama-assn.org/about/united-states-adopted-names/monoclonal-antibodies
5. United States Adopted Names Council. Previous approaches to monoclonal antibody nomenclature. American Medical Association. Accessed January 25, 2022. https://www.ama-assn.org/system/files/usan-previous-monoclonal-antibodies-policy.pdf
6. Doevendans E, Schellekens H. Immunogenicity of innovative and biosimilar monoclonal antibodies. Antibodies (Basel). 2019;8(1):21. doi: 10.3390/antib8010021
7. Lu RM, Hwang YC, Liu IJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27(1):1. doi: 10.1186/s12929-019-0592-z
8. Kopp-Kubel S. International nonproprietary names (INN) for pharmaceutical substances. Bull World Health Organ. 1995;73(3):275-279.
9. Mayrhofer P, Kunert R. Nomenclature of humanized mAbs: early concepts, current challenges and future perspectives. Hum Antibodies. 2019;27(1):37-51. doi: 10.3233/HAB-180347
10. United States Adopted Names: USAN council. American Medical Association. Accessed January 25, 2022. https://www.ama-assn.org/about/united-states-adopted-names/usan-council
11. World Health Organization. New INN monoclonal antibody (mAb) nomenclature scheme. Published November 2021. Accessed January 25, 2022. https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/new_mab_-nomenclature-_2021.pdf
12. Yu X, Cragg MS. Engineered antibodies to combat viral threats. Nature. 2020;588(7838):398-399. doi: 10.1038/d41586-020-03196-2
13. Ovacik M, Lin K. Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development. Clin Transl Sci. 2018;11(6):540-552. doi: 10.1111/cts.12567
14. Buie LW, Pecoraro JJ, Horvat TZ, Daley RJ. Blinatumomab: a first-in-class bispecific T-cell engager for precursor B-cell acute lymphoblastic leukemia. Ann Pharmacother. 2015 Sep;49(9):1057-67. doi: 10.1177/1060028015588555
15. Thillaivinayagalingam P, O’Donovan K, Newcombe AR, Keshavarz-Moore E. Characterisation of an industrial affinity process used in the manufacturing of digoxin-specific polyclonal Fab fragments. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;848(1):88-96. doi: 10.1016/j.jchromb.2006.03.065

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2022

The information presented is current as of January 25, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.