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New antibodies for cancer start clinical testing

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During 2014-2016, the pharmaceutical industry initiated first-in-human studies for an average of ~80 antibody-based therapeutics per year, and over 60% of these were designed to be treatments for cancer. The safety and tolerability of drugs are evaluated in Phase 1 studies, but preliminary efficacy may also be evaluated if the studies include patients rather than healthy volunteers. The anti-cancer antibodies new to the clinical pipeline in 2017 include two (CX-072, KN035) that target the programmed death-1 receptor ligand (PD-L1), and one each (CBT-501, FLYSYN) that target programmed death-1 receptor (PD-1) and Fms-like tyrosine kinase (FLT3), respectively.

PD-1 and PD-L1 are immune-checkpoint proteins that are frequently selected as targets for antibody therapeutics. Currently, two anti-PD-1 antibodies (pembrolizumab (Keytruda®), nivolumab (Opdivo®)) and two anti-PD-L1 antibodies (atezolizumab (Tecentriq®), avelumab (Bavencio®)) are approved for marketing, and one anti-PD-L1 antibody (durvalumab) is undergoing regulatory review. An additional 19 antibody-based therapeutics that target either PD-1 or PD-L1 are in clinical studies, with most (63%) in Phase 1 studies. Among these 19 are three antibodies, CX-072, KN035 and CBT-501, that recently entered their first clinical study. Developed by CytomX Therapeutics, CX-072 is a Probody targeting PD-L1. The first-in-human study (NCT03013491) of CX-072 as monotherapy and in combination with ipilimumab or with vemurafenib in patients with advanced or recurrent solid tumors or lymphomas started in January 2017. Probody therapeutics are designed to be activated by tumor-specific proteases, and thus may have minimal off-target effects. KN035, comprising an anti-PD-L1 single domain antibody fused with an Fc, is being evaluated in two Phase 1 studies (NCT02827968, NCT03101488) that started in 2017. Sponsored by 3D Medicines (Sichuan) Co., Ltd, the NCT02827968 study will evaluate the safety and tolerability of KN035 in patients with advanced and metastatic solid tumors, and the NCT03101488 study will evaluate and characterize the tolerability and safety profile of single agent KN035 in Chinese adults with unresectable advanced carcinoma. Anti-PD-1 CBT-501 (genolimzumab, GB-226) is a humanized IgG4 antibody with low antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity. A Phase 1 dose-escalation study (NCT03053466) sponsored by CBT Pharmaceuticals, Inc. of CBT-501 in patients with select advanced or relapsed/recurrent solid tumors was started in Australia in March 2017.
Developed by the University of Tübingen and SYNIMMUNE GmbH, FLYSYN is a chimeric antibody that targets the extracellular domain of FLT3 and is optimized for enhanced ADCC. The Phase 1 NCT02789254 study, which was initiated in February 2017, will evaluate the safety, tolerability and preliminary efficacy of FLYSYN for the treatment of acute myeloid leukemia patients with minimal residual disease.

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First approvals for ocrelizumab and dupilumab

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On March 28, 2017, the US Food and Drug Administration (FDA) granted first approvals for two monoclonal antibody (mAb) therapeutics, ocrelizumab (OCREVUS) and dupilumab (Dupixent®). Ocrelizumab is indicated for relapsing multiple sclerosis (MS) and primary progressive multiple sclerosis (PPMS), while dupilumab is a treatment for adults with moderate-to-severe eczema (atopic dermatitis).

Ocrelizumab (OCREVUS), a humanized IgG1 mAb targeting CD20, is the first drug approved by the FDA for PPMS. Ocrelizumab was granted FDA’s Breakthrough Therapy and Fast Track designations, and its application received priority review. A marketing application for ocrelizumab for the treatment of relapsing multiple sclerosis and primary progressive multiple sclerosis (MS) is being reviewed by the European Medicines Agency. The marketing applications are based on positive results from three Phase 3 studies, OPERA I (NCT01247324), OPERA II (NCT01412333), and ORATORIO (NCT01194570). Identical in their study design, OPERA I and OPERA II evaluated the efficacy and safety of 600 mg ocrelizumab intravenously (IV) administered every six months compared with 44 mg interferon beta-1a (Rebif®) subcutaneously administered 3 times per week in 1,656 people with relapsing forms of MS. Compared with Rebif®, ocrelizumab showed superior efficacy in reducing annualized relapse rates and disability progression sustained for at least three and for at least six months. The ORATORIO study evaluated the efficacy and safety of 600 mg ocrelizumab administered by IV infusion every six months compared with placebo in 732 people with primary progressive MS. Compared to patients who received placebo, patients who received ocrelizumab in this study showed significant reductions in disability progression sustained for at least three and for at least six months, as well as in other measures of progressive disease.

Dupilumab (Dupixent®), an anti-IL-4Ra IgG4 mAb, was granted Breakthrough Therapy designation for moderate-to-severe atopic dermatitis, and the biologics license application was granted a priority review by FDA. The safety and efficacy of Dupixent were established in three placebo-controlled clinical trials with a total of 2,119 adults with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). A marketing application for dupilumab is being reviewed by the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 28, 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, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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FDA approves brodalumab

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On February 15, 2017, the US Food and Drug Administration approved brodalumab (Siliq; Valent Pharmaceuticals International, Inc.) to treat adults with moderate-to-severe plaque psoriasis. Brodalumab, an IgG2 monoclonal antibody targeting the interleukin (IL)-17 receptor, inhibits the biological activity of IL-17A, IL-17F and other IL-17s. Labeling for brodalumab includes a Black Box Warning for the risks of suicidal thoughts or behavior. The product was approved with a Risk Evaluation and Mitigation Strategy (REMS) that includes prescriber and pharmacy certifications and informed consent by patients.

Brodalumab was granted its first marketing approval from the Ministry of Health, Labour and Welfare in Japan on July 4, 2016 for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis, and psoriatic erythroderma. The product’s brand name in Japan is Lumicef®. A marketing authorization application for brodalumab in psoriasis is undergoing evaluation by the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of February 16, 2017, marketing applications for a total of 12 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

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Free virtual issue featuring articles on neonatal Fc receptor is online now

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In a special issue of mAbs, Guest Editor Zita Schneider, D.V.M., Ph.D., Texas A&M Health Science Center, has compiled 12 articles describing recent results obtained about the neonatal Fc receptor, FcRn. All articles can be freely downloaded for a limited time. As a regulator of immunoglobulin G (IgG) and albumin homeostasis and a modulator of immune functions, this receptor has been attracting the interest of the scientific community and has become an unavoidable factor for consideration in the development of IgG- and albumin-based diagnostic and therapeutic reagents.

Burvenich et al. identified important amino acids playing a role in FcRn-IgG interaction, whereas Hironiwa et al. showed efficient antigen drop-off and IgG recycling utilizing calcium-dependent antigen-antibody binding. Ying and colleagues provided a tool to increase the transcytosis and half-life of engineered antibody domains through an FcRn-binding motif, whereas Meyer et al. utilized the albumin-binding characteristics of FcRn to generate IgA molecules with elongated half-life. Adams et al. used an anti-albumin Fv domain to extend the half-life of an Fab fragment, and Davé et al. used this domain to generate an Fab-dsFv bispecific antibody format.

FcRn can also serve as a screening tool for antibody selection as demonstrated by Souders et al. who developed a novel FcRn-binding biolayer interferometry assay, while Fan and colleagues used online peptide immune-affinity chromatography coupled with high resolution mass spectrometry to determine human FcRn expression levels in transgenic (Tg) mice and Avery et al. characterized these human FcRn Tg mice with respect to mAb pharmacokinetics (PK) prediction. Unverdorben et al. provided details of the PK of various Fc fusions compared to IgG molecules, Kelly et al. proved that FcRn-independent antigen-independent nonspecific interactions can also play a role in antibody PK, and Datta-Mannan et al. investigated several properties of mAbs in order to optimize PK parameters.

These articles provide valuable details to explore the possibilities offered by utilizing the functions of FcRn.

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mAb first approvals in 2017 may set a new record

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A new record for the number of monoclonal antibody (mAb) therapeutics granted their first marketing approval during a single year may be set in 2017. The previous record was set in 2015, when 8 antibody therapeutics were granted first approvals. Remarkably, 11 investigational mAb therapeutics are currently being considered for first marketing approvals that may be granted in 2017. Of these, 4 mAbs are under review as treatments for common immune-mediated disorders such as dermatitis, psoriasis and rheumatoid arthritis (anti-IL-6 sirukumab, anti-IL-6R sarilumab, anti-IL-4Ra dupilumab and anti- IL-23p19 guselkumab), 4 mAbs are under review as treatments for various types of cancer (anti-IL-1 alpha Xilonix, anti-CD22 inotuzumab ozogamicin, anti-PD-L1 avelumab and anti-PD-L1 durvalumab) and 3 mAbs are under review as treatments for other disorders (anti-CD20 ocrelizumab for multiple sclerosis, anti-sclerostin romosozumab for osteoporosis and anti-FGF23 burosumab for X-linked hypophosphatemia). Marketing applications for additional mAb therapeutics may be submitted to regulatory agencies during the first half of 2017, which could allow additional first approvals to occur during 2017.

Additional information on antibody therapeutics in Phase 3 clinical studies, regulatory review and those recently approved can be found in the ‘Antibodies to watch in 2017’ article, which can be freely downloaded.

The Antibody Society will post reports on the progress of mAb therapeutics during 2017, with an emphasis on first marketing application submissions and approvals in the European Union, United States and Japan. The Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. Please log in to access the table, located in the Members Only section.

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