The Antibody Society

the official website of the antibody society

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

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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Avelumab granted first approval

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On March 23, 2017, avelumab (Bavencio), an anti-PD-L1 human IgG1 mAb, was approved by the Food and Drug Administration (FDA) for treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma, which is a rare form of skin cancer. Avelumab was granted an accelerated approval, which FDA can grant for drugs for serious conditions to fill an unmet medical need using clinical trial data that is thought to predict a clinical benefit to patients. Under such an approval, additional clinical trials are required to confirm the clinical benefit. The biologics license application was granted Priority review and Breakthrough Therapy designation by FDA. Avelumab was granted a US orphan drug designation for Merkel cell carcinoma, which is diagnosed in ~ 1,600 people in the US every year. A marketing application for avelumab is undergoing evaluation by the European Medicines Agency, which also granted avelumab an orphan drug designation. The marketing applications for avelumab are based on data from the Phase 2 JAVELIN Merkel 200 study (NCT02155647), which demonstrated meaningful tumor responses in patients with metastatic disease that progressed after prior chemotherapy. Avelumab is also undergoing evaluation in Phase 3 studies of patients with other types of cancers, including non-small cell lung, renal cell, ovarian, gastric, breast and urothelial cancers.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 23, 2017, marketing applications for a total of 11 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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FcRn: are we done yet?

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The story of the neonatal Fc receptor (FcRn) started as a hypothesis made by F. W. Rogers Brambell more than half a century ago, when he predicted the existence of a saturable receptor responsible for protecting IgG molecules from degradation and the same or a similar system involved in IgG transport from mother to newborns. After its initial identification in neonatal rat intestine, FcRn indeed turned out to be the receptor responsible for these functions, but its further roles in albumin homeostasis and antigen presentation were also subsequently discovered (1-6).

While these properties have been widely exploited in the development of therapeutic and diagnostic reagents, the possible functions of FcRn are even broader. For example, further investigation of the immune functions of FcRn has revealed a role in anti-tumor responses. Intestinal dendritic cells expressing FcRn were shown to cross-present antigen derived from immune complexes, thereby activating tumor-specific T cells and eliciting immunity against colorectal cancer (7). More recently, it was also demonstrated that the presence of FcRn-expressing immune cells (macrophages and dendritic cells) in tumor samples was associated with a better prognosis in non-small cell lung cancer patients (8). A role for FcRn in cellular metabolism through its ability to recycle albumin has also been recently described. Specifically, low FcRn levels in tumor cell lines were associated with intracellular albumin accumulation and growth increase of tumor xenografts, whereas enforced expression of FcRn had the reverse effect (9). Despite these new results, FcRn likely has even more interesting features waiting to be revealed by enterprising scientists.


1, Rath et al, J Clin Immunol. 2013 Jan;33 Suppl 1:S9-17.
2, Challa et al, Curr Top Microbiol Immunol. 2014;382:249-72.
3, Sand et al, Front Immunol. 2015 Jan 26;5:682.
4, Pyzik et al, J Immunol. 2015 May 15;194(10):4595-603.
5, Stapleton et al, Immunol Rev. 2015 Nov;268(1):253-68.
6, Cervenak et al, Immunol Rev. 2015 Nov;268(1):269-87.
7, Baker et al, Immunity. 2013 Dec 12;39(6):1095-107.
8, Dalloneau et al, Oncotarget. 2016 Aug 23;7(34):54415-54429.
9, Swiercz et al, Oncotarget. 2017 Jan 10;8(2):3528-3541.

Update on antibody therapeutics in late-stage clinical studies

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Five monoclonal antibody (mAb) therapeutics have recently transitioned into late-stage clinical studies. Three (utomilumab, isatuximab, SHR-1210) are being evaluated as treatments for cancer, and the effects of two (crizanlizumab, olokizumab) are being studied in patients with other disorders.  Utomilumab (PF-05082566) is a human IgG2 antibody agonist that targets the extracellular domain of 4-1BB (CD137), which is a co-stimulatory receptor expressed on activated T cells. In preclinical studies, Fisher et al (1) demonstrated that utomilumab can activate NF-κB and induce downstream cytokine production, promote leukocyte proliferation, and inhibit tumor growth in a xenograft tumor model. Utomilumab is included in a multi-center, international, randomized, open label, 2-component (Phase 1b followed by Phase 3), parallel-arm study (Javelin DLBCL; NCT02951156) of avelumab in combination with various agents for the treatment of relapsed/refractory diffuse large B-cell lymphoma. The study includes a total of 5 arms (A: avelumab/utomilumab/rituximab; B: avelumab/utomilumab/azacitidine; C: avelumab/rituximab/bendamustine; D: selected regimen from Phase 1b component, which may be the agents investigated in study arms A or B or C; E: investigator’s choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin). Progression-free survival is the primary outcome measure of the Phase 3 component of the study, which has an estimated primary completion date of February 2021.

Isatuximab (SAR650984), a humanized anti-CD38 IgG1 mAb, is undergoing evaluation in a Phase 3 randomized, open-label, multicenter study (ICARIA-MM; NCT02990338) comparing the mAb in combination with pomalidomide and low-dose dexamethasone vs. pomalidomide and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. Jiang et al (2) demonstrated that isatuximab utilizes multiple mechanisms of action in mediating multiple myeloma cell cytotoxicity, and that pomalidomide augments this cytotoxicity. Progression-free survival is the primary outcome measure of the Phase 3 study, which has an estimated primary completion date of May 2018.

SHR-1210 is a humanized IgG4 antibody targeting programmed death-1. A randomized controlled multi-center Phase 2/3 study (NCT02989922) to evaluate SHR-1210 in patients with advanced hepatocellular carcinoma who failed or intolerable to prior systemic treatment is currently recruiting patients. The study will assess whether SHR-1210 treatment improves objective response rate and overall survival compared with the standard of care. The estimated primary completion date of the study is December 2018.

Crizanlizumab (SEG101, SelG1) is a humanized IgG2 P-selectin (CD62) inhibitor undergoing evaluation for prevention or reduction of the occurrence of pain crises in patients with sickle cell disease. Results from the Phase 2 SUSTAIN study (NCT01895361) showed that crizanlizumab administered at 5.0 mg/kg intravenously 14 times over a period of 52 weeks reduced the median annual rate of sickle cell-related pain crises by 45.3% compared to placebo (1.63 vs 2.98, p=0.010) (3). The median time to the first crisis was significantly longer in patients who received crizanlizumab compared with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). Crizanlizumab is listed as in Phase 3, with a planned filing date of 2020, in the Novartis Annual Report 2016.

Olokizumab, an anti-interleukin-6 humanized IgG4 mAb (4), is undergoing evaluation in three Phase 3 studies evaluating two doses of olokizumab (64 mg subcutaneous every 2 or 4 weeks) in patients with rheumatoid arthritis (RA). The primary outcome measures are the ACR20 response at Week 14. The Phase 3 NCT02760368 study (CREDO 1) will determine how safe and effective olokizumab is compared to placebo in RA patients who are already receiving, but not fully responding to, treatment with methotrexate. The study’s estimated primary completion date is May 2018. In study NCT02760407 (CREDO 2), the effectiveness and safety of olokizumab is being compared to placebo and adalimumab in RA patients who are taking methotrexate but have active disease. The study’s estimated primary completion date is January 2019. In study NCT02760433 (CREDO 3), the effects of olokizumab are being compared to placebo in patients with RA who are already receiving, but not fully responding to treatment with a tumor necrosis factor inhibitor (CREDO 3). The study’s estimated primary completion date is February 2019. Olokizumab, formerly known as CDP-6038, is under development by R-Pharm under a worldwide exclusive license from UCB Pharma S.A.

The Antibody Society maintains comprehensive tables that list mAbs in late-stage clinical studies (i.e., pivotal Phase 2, Phase 2/3 or Phase 3) for cancer and non-cancer indications. These tables are updated versions of Tables 3 and 4 in the article ‘Antibodies to watch in 2017’.  The tables will be updated with new information about antibody therapeutics that enter late-stage studies as the information is made available during the year. Information in bold was added during 2017. Antibody therapeutics that transition from late-stage studies to regulatory review are listed with the ‘Approved antibodies’ in the Members Only section of The Antibody Society’s website.

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1.       Fisher TS, et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother. 2012; 61(10):1721-33.

2.       Jiang H, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016; 30(2):399-408.

3.       Ataga KI, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017; 376(5):429-439.

4.       Shaw S, et al. Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs. 2014; 6(3):774-82.