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You are here: Home / Archives for cancer

Antibody Drug Conjugates – News

July 10, 2016 by Joost Melis

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%).

 

Filed Under: Ab news, ADC, Clinical pipeline Tagged With: ADC, Antibody drug conjugates, antibody therapeutics, cancer, clinical pipeline, GBM, NSCLC, SCLC, TNBC

Using bispecific antibodies for T-cell recruitment

June 13, 2016 by Janice Reichert

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.

 

Filed Under: Bispecific antibodies Tagged With: antibody therapeutics, bispecific, blinotuzumab, cancer, clinical pipeline, T cells

Atezolizumab: 4th mAb granted a first approval in 2016

May 23, 2016 by Janice Reichert

20150625-example-imageOn May 18, 2016, anti-PD-L1 atezolizumab (Tecentriq®) was approved by the Food and Drug Administration (FDA) as a treatment for patients with locally advanced or metastatic urothelial carcinoma. The marketing application for atezolizumab had received breakthrough therapy designation, priority review status and accelerated approval for this indication. A PD-L1 (SP142) assay complementary diagnostic to detect PD-L1 protein expression levels on the tumor-infiltrating immune cells of patients was also approved. An FDA action on a second application for use of atezolizumab as a treatment for patients with non-small cell lung cancer is expected by October 2016. Atezolizumab is the fourth antibody that inhibits an immune checkpoint to be granted a marketing approval. Two anti-PD1 antibodies, nivolumab (Opdivo®) and pembrolizumab (Keytruda®), were approved in 2014 in the US (2015 in the EU), and one anti-CTLA4 antibody, ipilimumab (Yervoy®), was approved in the US and EU in 2011. Atezolizumab is the fourth antibody product to be granted a first marketing approval in 2016.

Six additional antibody therapeutics (bezlotoxumab, sarilumab, brodalumab, Xilonix, begelomab, olaratumab) are now undergoing their first regulatory review in the European Union and the United States. If these antibodies are approved by the end of the year, the number of first approvals for antibody products in 2016 will set a new record (10 products), exceeding by 1 the previous record set in 2015. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the European Union and the Unites States. The antibody’s 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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Filed Under: Ab news, Approvals Tagged With: antibody therapeutics, approved antibodies, cancer

How long does anti-cancer antibody development take?

April 19, 2016 by Janice Reichert

mabs-coverA total of 15 antibody therapeutics were granted a first approval in the US during 2014-2015. Approximately half (53%) of these products were approved as treatments for cancers, including non-small cell lung cancer (necitumumab, nivolumab), melanoma (nivolumab, pembrolizumab), gastric cancer (ramucirumab), multiple myeloma (daratumumab, elotuzumab), acute lymphoblastic leukemia (blinatumomab) and neuroblastoma (dinutuximab). To aid development planning, we determined the mean and median elapsed time from entry into clinical study to first US approval for 7 of these 8 products. Dinutuximab was excluded because a substantial amount of the development was done by government or non-profit organizations. The mean (median) development time for the 7 products was 8.6 (8.9) years. The product with the shortest development time (4.6 years) was pembrolizumab (Keytruda®), which was the first approved antibody that targets the immune checkpoint PD-1. Pembrolizumab had FDA’s breakthrough therapy designation and orphan product designation, and its marketing application received a priority review and accelerated approval. The accelerated approval program allows FDA to approve a drug that treats a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate endpoint reasonably likely to predict clinical benefit to patients, but confirmatory clinical trials must be conducted after approval.
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Filed Under: Development metrics Tagged With: antibody therapeutics, cancer

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