The Antibody Society

the official website of the antibody society

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

Update on antibodies in regulatory review

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Antibody impressionA biologics license application (BLA) for romosozumab, an IgG2 monoclonal antibody targeting sclerostin, was recently submitted to the US Food and Drug Administration (FDA). The application includes data from the randomized, double-blind, placebo-controlled Phase 3 FRAME study (NCT01575834) of ~7,200 postmenopausal women with osteoporosis, defined as low bone mineral density at the total hip or femoral neck.  The study met the primary endpoint of reduction of the incidence of new vertebral fracture through 12 months in postmenopausal women with osteoporosis treated with romosozumab. The study also evaluated whether romosozumab treatment for 12 months followed by denosumab (Prolia®) treatment for 12 months, compared with placebo followed by denosumab treatment, reduced the risk of new vertebral fractures through 24 months; this endpoint was also met. The effects of romosozumab were compared to teriparatide (FORTEO®), a recombinant form of parathyroid hormone, in the randomized, open-label Phase 3 STRUCTURE study (NCT01796301). In this study, postmenopausal women with osteoporosis transitioning from bisphosphonate treatment who were administered romosozumab demonstrated a statistically significant increase in hip bone mineral density and strength compared with those who received teriparatide.

In other news, the FDA requested the submission of new data and analyses from the MODIFY I (NCT01241552) and MODIFY II (NCT01513239) clinical trials of bezlotoxumab, which has extended the review time on bezlotoxumab by three months, to October 23, 2016. Bezlotoxumab, a human IgG1 mAb that targets Clostridium difficile (C. difficile) toxin B, was evaluated for prevention of C. difficile infection recurrence. MODIFY I was a Phase 3, randomized, double-blind, placebo-controlled, adaptive design study of a single infusion of bezlotoxumab, an anti-C. difficile toxin A human monoclonal antibody (MK-3415, and the combination of bezlotoxumab + MK-3415 in patients receiving antibiotic therapy for C. difficile infection. The Phase 3 MODIFY II study compared only bezlotoxumab and the combination of bezlotoxumab + MK-3415 to placebo in patients receiving antibiotic therapy for C. difficile infection. The primary endpoint, the rate of C. difficile infection recurrence through week 12 compared to placebo, was met in both studies.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the European Union and United States. Of the 8 mAbs currently in regulatory review in these regions, 4 have FDA action dates known to occur in late October-December 2016. One additional mAb is likely to have an FDA action date by the end of 2016, based on the date of BLA submission and review status. Please log in to access the table, located in the Members Only section.

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Antibody Drug Conjugates – News

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square logo ADCImmunomedics announced the issuance of a novel patent (U.S. Patent 9,375,489) related to the company’s lead cancer therapeutic, sacituzumab govitecan, also known as IMMU-132. This antibody-drug conjugate (ADC) comprises a humanized antibody to the cancer target Trop-2 and is conjugated with SN-38, an active metabolite of the anti-cancer drug irinotecan. The patent entitled “Antibody-SN-38 Immunoconjugates with a CL2A Linker.” is the 28th issued U.S. patent covering the uses and composition of sacituzumab govitecan.

The ADC is in development for the treatment of patients with many diverse solid cancers. The most advanced indication in development is triple-negative breast cancer (TNBC). Phase II are also studies ongoing in patients with metastatic non-small-cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and in patients with metastatic urothelial cancers. According to Immunomedics’ updated clinical development plan for sacituzumab govitecan, in Q3 of 2016 the company plans to complete enrollment of additional patients into the ongoing single-arm Phase II study for patients with relapsed/refractory metastatic TNBC who received at least 2 prior therapies, including taxane. Immunomedics is collaborating with the FDA for completion of the ongoing Phase II trial and for submitting an Accelerated Approval registration application. Also discussions with the European Medicine Agency (EMA) have been initialized, and EMA has provided the company with advice on the scheduled Phase III trial.

 

In other news, AbbVie announced safety and preliminary efficacy data from a Phase I study of ABT-414. ABT-414 is an investigational ADC for treatment of epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM). Glioblastoma is the most common and most aggressive type of malignant primary brain tumor and in most cases a fatal disease. Amplified EGFR is the most common genetic mutation associated (~50% are EGFR mutations) with malignant GBM. With standard of care therapy, patients with GBM have a median survival of 15 months after diagnosis and two-year survival is 30%, demonstrating the urgent unmet need for new treatment options.

Published data showed no dose-limiting toxicities and frequent, reversible ocular toxicities. Furthermore, an estimated 30% (n=44) of patients treated with ABT-414 as monotherapy were progression free at six months [95% CI=17, 44] (secondary endpoint). Best Response Assessment in Neuro-Oncology (RANO) Criteria identified two partial responses, 18 patients with stable disease, and 24 with progressive disease for a total of 44 patients with complete data.

The most common serious adverse event (>1 patient) (n=48) was seizure (8%) as of January 7, 2016. Grade 3/4 treatment emergent adverse events (TEAEs) (>1 patient) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis (6%), hyperglycemia (6%), muscular weakness (6%), seizure (6%), blurred vision (4%) and ulcerative keratitis (4%).The most common TEAEs (≥25% patients) in this study arm were blurred vision (60%), headache (29%), photophobia (29%), dry eye (27%), eye pain (27%), and fatigue (27%).

 

Two antibodies in first regulatory review

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Antibody impressionFirst marketing applications were recently submitted for two novel antibody therapeutics, ocrelizumab and inotuzumab ozogamicin, intended as treatments for multiple sclerosis (MS) and CD22-positive acute lymphoblastic leukemia (ALL), respectively. Applications for ocrelizumab (OCREVUS), a humanized IgG1 antibody that targets CD20, as a treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) are undergoing regulatory review by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). No products are currently approved for both forms of MS. A priority review designation has been granted by FDA, and a first action on ocrelizumab’s biologics license application (BLA) is thus expected by December 28, 2016. The marketing applications are based on positive results from two identical Phase 3 studies (OPERA I and OPERA II) in people with RMS and the Phase 3 ORATORIO study in people with PPMS. All primary and key secondary endpoints were met in these three studies.

The antibody-drug conjugate inotuzumab ozogamicin targets CD22, an antigen found on the surface of cancer cells in most ALL patients. Results of a Phase 3 study evaluating the safety and efficacy of inotuzumab ozogamicin compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL were recently published in the New England Journal of Medicine. Improvements over chemotherapy on a number of measures, including complete hematologic remission and progression-free survival, were observed in this study. A marketing application for inotuzumab ozogamicin is undergoing review by the EMA; a BLA submission is likely. Inotuzumab ozogamicin received Breakthrough Therapy designation for ALL from FDA, and priority review of applications is a benefit of the designation, which suggests that an approval by FDA is thus possible by the end of 2016.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review (currently 8 mAbs) in the European Union and United States. The antibody target, format and year of first approval are included. Please log in to access the table, located in the Members Only section.

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Using bispecific antibodies for T-cell recruitment

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Post written by Whitney Shatz

T-cell recruitment for the treatment of cancer has garnered substantial interest over the past thirty years [1,2]. In this type of therapy, activated tumor-specific cytotoxic T-cell lymphocytes are directed to malignant tumor, and subsequently destroy them. Activation of this mechanism relies on T cells and tumor cells being in close proximity to one another. One popular strategy for bringing the cells together involves use of a bispecific antibody [3] where the dual-antigen specificity can enable simultaneous binding of a tumor-specific antigen along with an antigen present on a cytotoxic T-cell. In addition to having the advantage of enhanced functionality compared to a monospecific antibody, garnering dual specificity from single-agent therapy can simplify the development process, e.g., only one molecule needs to be approved. Two bispecific antibodies that take advantage of this principle have been approved: catumaxomab (Removab®) for the treatment of malignant ascites secondary to epithelial cancers and blinatumomab (Blincyto®) as second-line treatment for B cell acute lymphocytic leukemia (ALL).

Catumaxomab is a monoclonal IgG-like antibody [4]. It is termed trifunctional because one of the Fab arms binds epithelial tumor cells via the epithelial cell-adhesion molecule (EpCAM) antigen site, the other Fab arm binds cytotoxic T cells via the CD3 receptor, while the Fc acts as the third site of action, selectively engaging Fcγ receptor I-, IIa- or III on accessary cells. Thusly in this strategy, tumor cell destruction relies not only on T-cell lysis, but also on T-cell activation of accessory cells such as macrophages, dendritic cells and natural killer cells, which engage in destruction of tumor cells by various mechanisms such as perforin-mediated lysis, antibody-mediated phagocytosis and cytokine release. In 2009, catumaxomab became the first bispecific antibody to be approved, for use in Europe [4].

Blinatumomab, in contrast, is a bispecific T cell engager (BiTE) [5]. It is composed of two tandem single-chain variable fragments, each with unique specificity, fused together by a short flexible linker. One arm of this bispecific molecule binds CD3 on T cells while the other arm binds CD19, an antigen found on almost all B-lineage ALL cells and in many places throughout B cell differentiation. Bridging of the two antigens enables T-cell activation and exertion of cytotoxic activity by lysis of target B cells. Two advantages of this bispecific molecule are its small size, which results in fast systemic clearance and ensures close proximity of T cells to target cell, and its flexibility, which is thought to lead to efficient induction of T-cell activation by enabling optimal interaction with target epitopes on the two opposing cell membranes. In some cases, bifunctionality is preferred over trifunctionality because of concern that the Fc receptor interactions could potentially lead to dampening of the immune response.  In 2014, blinatumomab became the first bispecific antibody approved for use in the United States. It is currently being evaluated in Phase 2 clinical trials for the treatment of other ALL-related diseases [6].

Nonetheless despite very encouraging preclinical results [7-9] and extensive clinical activities [10-13], additional successful outcomes in the clinic have not been forthcoming. Of the twenty novel bispecific antibodies that entered first-in-humans clinical studies in 2014-2015, approximately half invoke a T-cell recruiting mechanism. Despite this abundance, none of these have advanced beyond Phase 1. Thus far, toxicity and lack of significant anti-tumor response appear to be the primary barriers to advancement of these agents. Improving the selectivity of T-cell activation is being examined as a way to address toxicity issues. To increase the effectiveness of the agents, alternate dose administration strategies are being tested. For example, blinatumomab’s dosing was changed to continuous infusion instead of intravenous injection to ensure continuous activation of T cells against target cells [14]. In addition, use of T-cell recruiting bispecific antibodies as first in-line treatment or as a component of combination therapies are also being evaluated to determine whether significant gains in patient response can be achieved. If such gains can be achieved with these approaches, more T-cell activating bispecific antibodies that will successfully meet patient needs may be available in the future.

1.        Staerz UD, Kanagawa O, Bevan M. Hybrid antibodies can target sites for attack by T cells. Nature 1985; 314:628–31.

2.        Perez P, Hoffman RW, Shaw S, Bluestone JA, Segal DM. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. Nature 1985; 316:354–6.

3.        Weidle UH, Kontermann RE, Brinkmann U. Tumor-antigen–binding bispecific antibodies for cancer treatment. Seminars in Oncology 2014; 41:653–60.

4.        Linke R, Klein A, Seimetz D. Catumaxomab: Clinical development and future directions. mAbs 2014; 2:129–36.

5.        Wolf E, Hofmeister R, Kufer P, Schlereth B, Baeuerle PA. BiTEs: bispecific antibody constructs with unique anti-tumor activity. Drug Discovery Today 2005; 10:1237–44.

6.        Turner J, Schneider S. Blinatumomab: A new treatment for adults with relapsed acute lymphocytic leukemia. Clin J Oncol Nurs. 2016; 20:165–8.

7.        Deo YM, Sundarapandiyan K, Keler T, Wallace PK, Graziano RF. Bispecific molecules directed to the Fc receptor for IgA (FcαRI, CD89) and tumor antigens efficiently promote cell-mediated cytotoxicity of tumor targets in whole blood. J Immunol 1998; 160:1677–86.

8.        Löffler A, Kufer P, Lutterbüse R, Zettl F, Daniel PT, Schwenkenbecher JM, Riethmüller G, Dörken B, Bargou RC. A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. Blood 2000; 95:2098–103.

9.        Heiss MM, Ströhlein MA, Jäger M, Kimmig R, Burges A, Schoberth A, Jauch K-W, Schildberg F-W, Lindhofer H. Immunotherapy of malignant ascites with trifunctional antibodies. Int J Cancer 2005; 117:435–43.

10.      Begent RH, Verhaar MJ, Chester KA, Casey JL, Green AJ, Napier MP, Hope-Stone LD, Cushen N, Keep PA, Johnson CJ, et al. Clinical evidence of efficient tumor targeting based on single-chain Fv antibody selected from a combinatorial library. Nat Med 1996; 2:979–84.

11.      Burges A, Wimberger P, Kümper C, Gorbounova V. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM× anti-CD3 antibody: a phase I/II study. Clin Cancer Res. 2007; 13:3899-905.

12.      De Gast GC, Van Houten AA, Haagen IA, Klein S, De Weger RA, Van Dijk A, Phillips J, Clark M, Bast BJ. Clinical experience with CD3 X CD19 bispecific antibodies in patients with B cell malignancies. J Hematother. 1995;4:433-7.

13.      Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, Dudnichenko AS, Aleknaviciene B, Razbadauskas A, Gore M, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer 2010; 127:2209–21.

14.      Klinger M, Brandl C, Zugmaier G, Hijazi Y, Bargou RC, Topp MS, Gökbuget N, Neumann S, Goebeler M, Viardot A, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab. Blood 2012; 119:6226–33.