Janice Reichert, Author at The Antibody Society

First approval for bezlotoxumab, a new antibody therapeutic for reduction of C. difficile infection recurrance

October 23, 2016 by Janice Reichert

Bezlotoxumab (ZINPLAVA) was approved by the US Food and Drug Administration to reduce recurrence of Clostridium difficile infection (CDI) in adult patients (18 years of age or older) who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence. The product is a human IgG1 monoclonal antibody that targets C. difficile toxin B, and it is the first monoclonal antibody therapeutic to be approved for reduction of recurrence of a bacterial infection. Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and was licensed to Merck in 2009.

Bezlotoxumab is the 6th new antibody therapeutic to be granted a first approval in 2016. Of the applications for 8 new mAb therapeutics currently undergoing regulatory review in the US or EU (i.e., mAbs not previously approved for any indication in these regions), 3 have FDA action dates known to occur in late October-December 2016. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the US or EU. Please log in to access the table, located in the Members Only section.

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Bispecifics: shaking up the antibody product landscape

October 20, 2016 by Janice Reichert

Post written by Maarten Janmaat & Janine Schuurman

The antibody product landscape is continuously changing : more potent formats including antibody-drug conjugates and bispecific antibodies are on the rise (1). Although the concept of bispecifics has been known for more than 30 years, many technical challenges have only been resolved in recent years, resulting in bispecifics in different flavors entering the clinic. Numerous platforms, each with their own specific functional characteristics and manufacturing requirements, have led to two approved bispecific antibody products, catumaxomab and blinatumomab, and >50 bispecific antibody products in clinical evaluations (Figure 1). Roughly, the landscape of bispecific antibody platforms can be divided over 3 major classes: fragments, symmetric and asymmetric antibodies. Products representative of all 3 classes have reached the stage of clinical evaluation (Figure 2).

Multi-targeting approaches, including bispecifics, are generally being recognized to address disease heterogeneity and therapy escape. We believe, however, that the real excitement in the field of bispecific antibodies comes from the ability to couple two (or more) specificities, thereby introducing novel functionalities that were not present in the parent molecules. This class is also termed “obligatory bispecifics” by Spiess et al (2) and Labrijn et al (3).

Well-known examples of obligatory bispecifics, and the most validated use, are CD3 bispecifics, which activate T cells solely when bound in close proximity to a target-expressing cell, resulting in specific and effective tumor-cell killing. The two clinical approved therapeutics, catumaxomab and blinatumomab, belong to this class.

Another example of an innovative bispecific application is emicizumab (Chugai), which crosslinks Factor IXa and Factor X and mimics the natural function of Factor VIIIa. This Factor VIII replacement therapy is currently in a Phase 3 clinical trial in hemophilia patients (NCT02622321).

Bispecifics can also be used to guide translocation to immune-privileged sites, such as the human brain. Yu et al have described a molecule that binds with one arm to the transferrin receptor, which guides crossing over the endothelium (4). Upon accessing the brain, the molecule binds to its therapeutic target β-secretase (BACE1), resulting in reduction of brain amyloid-β.

Recently, Wec et al. presented a very elegant ’Trojan horse’ bispecific approach to target Ebola infections (5). By combining knowledge of the molecular mechanisms of filovirus infection and the availability of mAbs against relevant epitopes, a molecule was generated that binds to a conserved surface-exposed Ebola epitope with one domain, while the second binding domains attacks the receptor binding site within the endosomal compartment upon internalization, thereby preventing viral entry.

Some other interesting uses of obligatory bispecifics include enhanced lysosomal delivery of antibody-drug conjugates by targeting lysosomal membrane protein CD63 in combination with a tumor-specific target (6), fixing HER2 receptors in a conformational state (7) and induction of tumor cell DR5 clustering by using simultaneously binding to fibroblasts (8).

Taken together, technical progresses in the past years has advanced the development of therapeutic bispecific into the clinic. In particular, obligatory bispecifics offer exciting and innovative treatment opportunities by revealing completely new functionalities.

What ideas do you have?

References
1.            J. Schuurman, P. W. Parren, Curr Opin Immunol 40, vii (Jun, 2016).
2.            C. Spiess, Q. Zhai, P. J. Carter, Mol Immunol 67, 95 (Oct, 2015).
3.            A. Labrijn, P. W. Parren, Science in press, (2016).
4.            Y. J. Yu et al., Sci Transl Med 3, 84ra44 (May 25, 2011).
5.            A. Z. Wec et al., Science, (Sep 8, 2016).
6.            B. E. de Goeij et al., Mol Cancer Ther, (Aug 24, 2016).
7.            C. Jost et al., Structure 21, 1979 (Nov 5, 2013).
8.            P. Brunker et al., Mol Cancer Ther 15, 946 (May, 2016).

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First approval for olaratumab, a new antibody therapeutic for sarcoma

October 20, 2016 by Janice Reichert

Olaratumab (Lartruvo®) was granted an accelerated approval for treatment, with doxorubicin, of adults with soft tissue sarcoma by the US Food and Drug Administration on October 19, 2016. This new monoclonal antibody (mAb) therapeutic targets platelet-derived growth factor receptor-α. The approval was granted in part based on results of a clinical study that compared administration of doxorubicin alone with the combination of olaratumab with doxorubicin. In this study, median overall survival was 14.7 vs. 26.5 months for patients who received doxorubicin alone vs. those who received the combination of drugs. Olaratuzumab’s application was granted numerous FDA designations intended to facilitate the development of new drugs, especially those for serious or life-threatening diseases, including Fast Track and Breakthrough Therapy designations, and priority review. The product also received orphan drug designations in both the US and European Union (EU). On September 15, 2016, the European Medicines Agency’s Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for olaratumab for the treatment of advanced soft tissue sarcoma. A decision by the European Commission is pending.

Olaratumab is the 5th new antibody therapeutic to be granted a first approval in 2016. Of the applications for 9 new mAb therapeutics currently undergoing regulatory review in the US or EU (i.e., mAbs not previously approved for any indication in these regions), 4 have FDA action dates known to occur in late October-December 2016. The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the US or EU. Please log in to access the table, located in the Members Only section.

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Antibody-drug conjugates in the spotlight

October 14, 2016 by Janice Reichert

Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic agents into targeted cells, and they are typically developed as treatments for cancer. Due to the need for new cancer drugs, the development of ADCs is the focus of substantial efforts by the biopharmaceutical industry. Nearly 60 ADCs are currently in clinical studies, one ADC, inotuzumab ozogamicin, is undergoing regulatory review, and three ADCs have been granted approvals, although the first to be approved, gemtuzumab ozogamicin (Mylotarg®) was withdrawn from the market in 2010.

Two ADCs, brentuximab vedotin (Adcetris®) and ado-trastuzumab emtansine (Kadcyla®), are currently marketed in the United States (US) and European Union (EU), as well as other countries. These two ADCs are disparate in their composition, and are used as treatments for different indications. Brentuximab vedotin is composed of an anti-CD30 monoclonal antibody (mAb) conjugated to the tubulin inhibitor monomethyl auristatin E via a valine-citruline dipeptide linkage designed for conditional cleavage inside cells. In contrast, ado-trastuzimab emtansine comprises an anti-human epidermal growth factor receptor-2 (HER2) mAb coupled to the tubulin-disrupting maytansinoid DM1 drug via a non-reducible thioether linkage. Brentuximab vedotin was granted its first approval in 2011 for two indications: 1) classical Hodgkin lymphoma after failure of autologous hematopoietic stem cell transplantation or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates; and 2) systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The first approval for ado-trastuzumab emtansine was granted in 2013; the product is indicated for the treatment of HER2-positive metastatic breast cancer in patients who previously received trastuzumab and a taxane separately or in combination.

Of the nearly 60 ADCs in the clinic, only two (depatuxizumab mafodotin, vadastuximab talirane) are currently in late-stage (Phase 2/3 or 3) clinical studies, but two additional ADCs (sacituzumab govitecan, mirvetuximab soravtansine) may transition to Phase 3 soon. Depatuxizumab mafodotin (ABT-414) is composed of an anti-epidermal growth factor receptor (EGFR) mAb conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl linker. The Phase 2b/3 Intellance 1 study (NCT02573324) of the ADC with concurrent chemoradiation and adjuvant temozolomide in adult patients with newly diagnosed glioblastoma multiforme (GBM) with EGFR amplification was initiated in late 2015. Depatuxizumab mafodotin has orphan drug designations for GBM in the US and glioma in the EU, and it was granted a US Rare Pediatric Disease Designation for pediatric EGFR-amplified diffuse intrinsic pontine glioma, a brainstem tumor that is highly aggressive and difficult to treat. Vadastuximab talirane (SGN-33A) is an anti-CD33 mAb with 2 engineered cysteine residues through which DNA cross-linking pyrrolobenzodiazepine dimer drug moieties are conjugated via a protease-cleavable valine-alanine dipeptide linker. The Phase 3 CASCADE clinical trial (NCT02785900) of vadastuximab talirine in combination with azacitidine (Vidaza) or decitabine (Dacogen) in older patients with newly diagnosed acute myeloid leukemia (AML) was initiated in May 2016. Results from a Phase 1 study indicated that the ADC in combination with hypomethylating agents was a well-tolerated regimen with a high remission rate in older patients with AML.

The transitions of sacituzumab govitecan (IMMU-132) and mirvetuximab soravtansine (IMGN853) to Phase 3 may occur by the end of 2016. The start of a Phase 3 study (NCT02574455) that will evaluate the safety and efficacy of sacituzumab govitecan in refractory/relapsed triple-negative breast cancer (TNBC) patients is scheduled for December 2016. This ADC has received US Breakthrough Therapy and Fast Track designations for the treatment of patients with TNBC. Sacituzumab govitecan comprises an anti-TROP-2 mAb conjugated via a pH-sensitive linker to SN-38, the active metabolite of the chemotherapeutic irinotecan, in a site-specific manner. Mirvetuximab soravtansine is being assessed as a single-agent therapy in the FORWARD I trial (NCT02631876) of the ADC versus investigator’s choice of chemotherapy in adults with folate receptor (FR)-α positive advanced epithelial ovarian cancer, primary peritoneal cancer or primary fallopian tube cancer, which is being changed from a Phase 2 to a Phase 3 trial. Mirvetuximab soravtansine is composed of an anti-FRα mAb linked to the tubulin-disrupting maytansinoid DM4 via a cleavable linker.

It should be noted that, despite the increased complexity of the molecules, ADCs are also the focus of companies developing biosimilar products. As discussed in previous Society posts, biosimilars of antibody-based drugs that have lost patent protection, including adalimumab (Humira®), rituximab (Rituxan®, Mabthera®), trastuzumab (Herceptin®) and etanercept (Enbrel®), are already approved or undergoing regulatory review in the US and EU, as well as other countries.

The Antibody Society thanks Hanson Wade for access to Beacon, the World ADC database.

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FDA approves Amjevita® (adalimumab-atto) as a biosimilar to Humira®

September 23, 2016 by Janice Reichert

The US Food and Drug Administration has approved Amjevita® (adalimumab-atto) as a biosimilar to Humira® (adalimumab). In adult patients, Amjevita® is approved for moderately to severely active rheumatoid arthritis; active psoriatic arthritis; active ankylosing spondylitis (an arthritis that affects the spine); moderately to severely active Crohn’s disease; moderately to severely active ulcerative colitis; and moderate to severe plaque psoriasis. Amjevita® is also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.
Amjevita® is the third antibody-based drug to gain approval as a biosimilar in the US this year. Inflectra® (infliximab-dyyb), a biosimilar to Remicade® (infliximab), was approved in April 2016 and Erelzi® (etanercept-szzs) , a biosimilar to Enbrel® (etanercept), was approved in August 2016.

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