The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

First approval for guselkumab

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On July 13, 2017, the Food and Drug Administration (FDA) approved the biologics license application for guselkumab (TREMFYA). The product, a human IgG1 monoclonal antibody targeting interleukin-23, is indicated for the treatment of patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Approval was based on results from a clinical development program that included more than 2,000 patients in the Phase 3 VOYAGE 1, VOYAGE 2 and NAVIGATE studies. Guselkumab was generated using MorphoSys’ Human Combinatorial Antibody Library technology.

As of July 13, guselkumab is the eighth antibody therapeutic to be granted a first marketing approval in any country in 2017, following the approvals of brodalumab, avelumab, ocrelizumab, dupilumab, durvalumab, sarilumab and inotuzumab ozogamicin. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of July 13, 2017, marketing applications for a total of nine antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, a marketing application for the antibody-drug conjugate gemtuzumab ozogamicin, which was approved in 2000 by the US FDA and subsequently withdrawn from the US market, is undergoing review in the EU and US.

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First approval for inotuzumab ozogamicin in the European Union

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The European Commission has granted a marketing approval for the antibody-drug conjugate (ADC) inotuzumab ozogamicin (BESPONSA) as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL). Inotuzumab ozogamicin is a CD22-targeting humanized IgG4 antibody conjugated to the drug calicheamicin via an acetyl butyrate linker. The approval of BESPONSA was supported by results from the Phase 3 INO-VATE ALL trial (ClinicalTrials.gov number NCT01564784), which compared the effects of either inotuzumab ozogamicin or standard intensive chemotherapy in adults with relapsed or refractory ALL Results of this study were published in The New England Journal of Medicine in 2016. A biologics license application for inotuzumab ozogamicin for the treatment of adult patients with relapsed or refractory B-cell precursor ALL is undergoing a priority review by the US Food and Drug Administration (FDA); the goal date for their decision is in August 2017.

As of July 1, inotuzumab ozogamicin is the seventh antibody therapeutic to be granted a first marketing approval in any country in 2017, following the approvals of brodalumab, avelumab, ocrelizumab, dupilumab, durvalumab, and sarilumab. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of July 1, 2017, marketing applications for a total of 10 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, a marketing application for the ADC gemtuzumab ozogamicin, which was approved in 2000 by the US FDA and subsequently withdrawn from the US market, is undergoing review in the EU and US.

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Importance of isoelectric point (pI) of antibodies

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One important characteristic of monoclonal antibodies (mAbs) is their isoelectric point (pI), which essentially is the pH at which the antibody has no net electrical charge, and its value depends on the charged amino acids the antibody contains. If the pH of the surrounding environment is below the antibody’s pI, then the molecule carries a net positive charge, whereas the antibody will carry a net negative charge when the pH is above the pI.

When assessing pharmacokinetic (PK) properties of therapeutic antibodies not only the target-mediated drug disposition (TMDD) but also non-target-related mechanisms influence overall PK behavior and pI can be an important factor of the latter. Since the surface of most cells is negatively charged, antibodies need to be positively charged for efficient fluid-phase endocytosis (pinocytosis), therefore the environmental pH needs to be below the pI of the antibody. Therapeutic antibodies with pI values in the range of 8-9 are taken up adequately after administration since the physiological pH is 7.4, however, in some cases antibodies have a pI outside of this range or have been manipulated to achieve increased or decreased pI values (cationization or anionization, respectively). It is generally observed that increases in net positive charge of antibodies result in increased blood clearance and increased tissue retention with shorter half-life, whereas antibodies with lower pI generally have decreased tissue uptake and longer half-life (1-3), although observations can be conflicting regarding correlation between mAb clearance and pI (4). Even subtle manipulation such as molecular surface remodeling to disrupt positive patch regions can influence PK properties (5). In summary, pI of mAbs is known to have a substantial effect on PK behavior independent of recycling mediated by the neonatal Fc receptor, FcRn. Small changes of pI during the routine manufacturing of mAb charge variants, however, are not expected to result in dramatic changes and may not require extensive analyses (6). In any case, it is encouraged that pI values are reported in studies as an important factor influencing antibody behavior. Furthermore, since selecting the best candidates during early preclinical phases of product development can substantially decrease time and cost of development, it is of great importance to consider de-risk strategies and tools during drug discovery and development, including antibody variable region charge and antibody pI analyses (7-9). A new analytical platform has been recently described and validated on seven mAbs to rapidly assess and rank mAb charge variants during early stage development, which can be a useful screening technique during early stage development (10).

References:

1 Boswell et al, Bioconjug Chem. 2010 Dec 15;21(12):2153-63.
2 Igawa et al, Protein Eng Des Sel. 2010 May;23(5):385-92.
3, Li et al, MAbs. 2014;6(5):1255-64.
4, Hötzel et al, MAbs. 2012 Nov-Dec;4(6):753-60.
5, Datta-Mannan et al, MAbs. 2015;7(3):483-93.
6, Khawli et al, mAbs, 2010;(2)6:613-624.
7, Bumbaca Yadav et al, J Biol Chem. 2015 Dec 11;290(50):29732-41.
8, Dostalek et al, MAbs. 2017 May 2:1-11.
9, Jarasch et al, J Pharm Sci. 2015 Jun;104(6):1885-98.
10, Wagner-Rousset, J Chromatogr A. 2017 May 19;1498:147-154.

The source infix is out!

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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. Although the change was officially announced today, 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 that will be published in the upcoming August/September 2017 issue of mAbs. Society members will be alerted by email when this article is available for downloading from the ‘Latest Articles’ section of the mAbs website.

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Updates on sarilumab, erenumab, romosozumab and XBiotech’s candidate antibody

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On May 22, 2017, the Food and Drug Administration (FDA) granted an approval for sarilumab (Kevzara) for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease modifying antirheumatic drugs, such as methotrexate (MTX). Sarilumab is a human monoclonal antibody (mAb) that targets interleukin-6 receptor (IL-6R), and has been shown to inhibit IL-6R-mediated signaling. Sarilumab was first approved on January 12, 2017 for the treatment of adult patients with moderately to severely active RA by Health Canada.

On May 18, 2017, Amgen announced that a biologics license application (BLA) for erenumab was submitted to the FDA. Erenumab is a human mAb targeting calcitonin gene-related peptide receptor. The BLA includes data from pivotal studies investigating the efficacy of erenumab versus placebo in reducing the number of migraine days for patients with episodic and chronic migraine.

On May 21, 2017, Amgen and UCB announced that the Phase 3 ARCH (Active-contRolled FraCture Study in Postmenopausal Women with Osteoporosis at High Risk of Fracture) study of romosozumab in postmenopausal women with osteoporosis at high risk for fracture based on previous fracture history met both primary endpoints and the key secondary endpoint. At the primary analysis, treatment with romosozumab for 12 months followed by alendronate significantly reduced the incidence of new vertebral fractures through 24 months, clinical fractures (primary endpoints) and non-vertebral fractures (key secondary endpoint) in postmenopausal women with osteoporosis at high risk for fracture, compared to alendronate alone. An imbalance in positively adjudicated cardiovascular serious adverse events was observed as a new safety signal (2.5% romosozumab vs 1.9% alendronate at 12 months). Overall adverse events and serious adverse events were generally similar between the treatment groups throughout the ARCH study and also in the initial 12-month romosozumab treatment period. No imbalance in cardiovascular serious adverse events was seen in the 7,180-patient placebo-controlled FRAME (FRActure study in postmenopausal woMen with ostEoporosis) study. Regulatory submissions for romosozumab based on the FRAME study results are currently under review with the FDA, Health Canada and the Pharmaceuticals and Medical Devices Agency in Japan. Amgen has agreed with the FDA that the ARCH data should be considered in the regulatory review prior to the initial marketing authorization, and as a result Amgen does not expect approval of romosozumab in the US to occur in 2017.  Amgen has indicated that engagement with PMDA and Health Canada will occur as part of the ongoing review process, and preparation for the European regulatory submission will continue as planned.

On May 18, 2017, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a negative opinion, recommending the refusal of the marketing authorization for human IgG1 monoclonal antibody specific for human interleukin-1 alpha XBiotech, intended for treating debilitating symptoms of advanced colorectal cancer. CHMP opinion was based on data from a study in 333 patients that evaluated the effects of the mAb vs placebo on lean body mass and quality of life. The committee noted that the study did not show clear improvements in either lean body mass or quality of life, and there was an increased risk of infection in patients taking the medicine, which was not considered acceptable in vulnerable patients who will be receiving palliative care. There were also inadequate controls of the manufacturing process to ensure the medicine would have the same quality as the product used in clinical trials. Therefore, the CHMP was of the opinion that the benefits of this medicine did not outweigh its risks. The EMA marketing authorization application procedure includes an appeal process. XBiotech Inc. has indicated that they may seek access to this process at the appropriate time.

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