The AIRR-II Community Meeting was held 27-30 June 2016 at the NIH Fishers Lane facility. Please visit the Introduction and Agenda page for more information and click on videos for recordings of the six sessions at NIH.
Using bispecific antibodies for T-cell recruitment
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.
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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.
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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.
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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.
European Medicines Agency’s antibody PRIority MEdicines
On June 1, the European Medicines Agency (EMA) announced that four medicines in development were accepted under their new PRIority MEdicines (PRIME) scheme, which focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options. In this voluntary scheme, EMA offers early, proactive and enhanced support to developers to optimize the generation of robust data on a medicine’s benefits and risks, and enable accelerated assessment of medicine applications. Early clinical data that shows a medicine has the potential to benefit patients with unmet medical needs must be provided for it to be accepted for PRIME access.
Of the four medicines given PRIME access to date, two, aducanumab and NI-0501, are antibody therapeutics. Aducanumab, which targets amyloid beta, has PRIME access as a treatment of Alzheimer’s disease. The antibody is currently being evaluated in two Phase 3 studies of patients with early Alzheimer’s disease. The primary objective of the studies is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment. An estimated 1350 patients will be enrolled in each study. Both studies were initiated in 2015, and have primary completion dates in February 2020.
NI-0501, a human mAb targeting interferon gamma, has PRIME access as a treatment of primary hemophagocytic lymphohistiocytosis (PHL). A Phase 2, open-label, single arm study to explore the safety, tolerability, pharmacokinetics and efficacy of intravenous multiple administrations of NI-0501 in children with PHL is currently recruiting patients. The study was initiated in 2013 and has an estimated enrollment of 10 patients. The primary completion date of the study is December 2016. NI-0501 has orphan drug designations in the European Union and United States. It also has the US Food and Drug Administration’s Breakthrough Therapy Designation, which, like the PRIME scheme, is intended to expedite the development and review of new therapies for serious or life threatening conditions that have shown encouraging early clinical results over available therapies.
Find information about the four medicines accepted under the PRIME scheme here.
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New antibody therapeutics for multiple sclerosis
On May 27, 2016 the Food and Drug Administration (FDA) approved daclizumab (Zinbryta®) for the treatment of adults with relapsing forms of multiple sclerosis (MS). The product, which targets interleukin-2 receptor alpha chain (CD25), is manufactured using a high-yield process. Daclizumab (Zenapax®) was first approved in 1997 for the prevention of organ transplant rejection. While the two products have the same amino acid sequence, Zinbryta has a different glycosylation pattern and reduced antibody-dependent cytotoxicity compared to Zenapax. Zinbryta’s approval was based in part on the results of the Phase 3 DECIDE study (NCT01064401) of Zinbryta versus interferon β 1a (Avonex®) in patients with relapsing-remitting MS. In this study, patients administered Zinbryta experienced fewer clinical relapses than those who received Avonex (annualized relapse rate 0.22 vs. 0.39; 45% lower rate with Zinbryta; P<0.001). Due to serious safety risks, FDA has included a boxed warning on the product label, and it is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.
Another antibody therapeutic, ocrelizumab, has been evaluated in a Phase 3 study of patients with primary progressive multiple sclerosis (PPMS). The antibody targets CD20 on B cells, which are implicated in the inflammatory and neurodegenerative processes of MS. Ocrelizumab was granted FDA’s Breakthrough Therapy Designation for PPMS, which is a debilitating form of MS characterized by steadily worsening symptoms. PPMS patients typically do not experience distinct relapses or periods of remission. Currently, no treatments are approved for treatment of the disease. In the pivotal Phase 3 ORATORIO study, treatment with ocrelizumab significantly reduced disability progression and other markers of disease activity compared with placebo. Ocrelizumab is also undergoing evaluation in Phase 3 studies of patients with relapsing-remitting forms of the disease. Genentech plans to submit a marketing application for ocrelizumab as a treatment for MS in 2016. If an application is submitted to FDA by the end of June and receives a priority review, which is a benefit of the Breakthrough Therapy Designation, then ocrelizumab could be approved for marketing in the US by the end of 2016.
Antibody Drug Conjugates – Clinical Progress
In the second half of May several companies reported important progress on their therapeutic ADC products. The Dutch pharmaceutical company Synthon initiated the second phase of the ongoing phase I clinical trial with its investigational anti-HER2 ADC SYD985. During the first part patients with solid tumors of any origin were enrolled. Promising results were obtained in this dose-finding part of the trial in 33 cancer patients who were dosed with between 0.3 and 2.4 mg/kg of SYD985 every three weeks. Very high response rates and durable responses were observed at doses from 1.2 mg/kg onwards in patients whose cancers were refractory to HER2-targeted agents, including Herceptin® and Kadcyla®. The second part will see 48 additional heavily pre-treated patients with HER2-positive breast cancer enrolled into the Phase I trial. This marked a significant next step in the development of SYD985, the frontrunner of the company’s duocarmycin-based ADC platform.
Additionally, Seattle Genetics announced initiation of a pivotal phase III clinical trial, CASCADE, evaluating vadastuximab talirine (SGN-CD33A) in combination with azacitidine (Vidaza) or decitabine (Dacogen) in older patients with newly diagnosed acute myeloid leukemia (AML). SGN-CD33A is an ADC targeting CD33 comprising an engineered cysteine antibody (EC-mAb) stably linked to a pyrrolobenzodiazepine (PBD) dimer. CD33 is expressed on leukemic blasts in nearly all AML patients and expression is generally consistent regardless of age, cytogenetic abnormalities or underlying mutations. Azacitidine and decitabine are hypomethylating agents (HMAs) commonly used in the treatment of older AML patients. The phase III CASCADE study is a randomized, double-blinded, placebo-controlled, global clinical trial. Patients will be randomized on a 1:1 ratio to be treated with an HMA plus SGN-CD33A or an HMA plus placebo. The secondary endpoints include the comparison of composite complete remission rate, event-free and leukemia-free survival, duration of response, safety, and 30- and 60-day mortality rates. This phase III trial will enroll approximately 500 patients globally.
