The Antibody Society

the official website of the antibody society

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

Atezolizumab: 4th mAb granted a first approval in 2016

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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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Antibody Drug Conjugates – Acquisitions and Partnering

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AbbVie dominated the news in the last weeks of April after announcing the acquisition of Stemcentrx including the company’s late-stage rovalpituzumab tesirine (Rova-T) for $5.8bn. Furthermore, AbbVie partnered up with CytomX to jointly develop and commercialize a probody-drug conjugate (PDC) against CD71.

Stemcentrx’ Rova-T, also known as SC16LD6.5, is addressing small cell lung cancer (SCLC) and other neuroendocrine cancers such as large cell neuroendocrine carcinoma. Rova-T has received orphan drug designation from the FDA for treatment of small cell lung cancer. Rova-T targets delta-like protein 3 (DLL3), which is expressed in >80% SCLC patient tumors and is not present on healthy tissue. Rova-T comprises a D6.5 pyrrolobenzodiazepine (PBD) payload conjugated to cysteine residues on the SC16 antibody, a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with an average drug-to-antibody ratio (DAR) of 2. Rova-T represents a multi-billion dollar peak revenue opportunity with expected commercialization in 2018. The acquisition expands AbbVie’s oncology pipeline with four additional early-stage clinical compounds in solid tumor indications and Stemcentrx’ portfolio of preclinical assets.

 

Together with CytomX, AbbVie will co-develop a PDC against CD71. PDCs contain a masking peptide designed to decreasing target binding to healthy tissue and remain inactive until the molecules are activated proteolytically in the tumor microenvironment, thereby minimizing toxicities. The target, transferrin receptor 1 (TfR1), also known as CD71, is ubiquitously expressed on dividing, normal or healthy cells plus a number of hematologic and solid malignant cancer cells. CD71 mediates transferrin-iron complex uptake, an essential process for cell division and therefore also for tumors. CD71 is homogeneously and highly expressed (3+ expression assessed by IHC) in almost all tumor types, including metastatic tumors. The current PDC approach should avoid targeting the many healthy cell types that also express CD71.

 

Additionally, Regeneron Pharmaceuticals and MedImmune (wholly owned subsidiary of  AstraZeneca) entered into a licensing agreement under which Regeneron will use MedImmune’s PBD-based payload and linker technology to develop ADCs against a number of cancer targets. MedImmune will have the option to develop and commercialize certain products created with this technology in territories outside of the United States.

Antibody immune checkpoint modulators in the clinic

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Antibody impressionThe possibility of using antibody therapeutics to modulate immune checkpoint pathways has captured the attention of many organizations involved in the research and development of cancer drugs. As of early May 2016, three antibody checkpoint inhibitors (ipilimumab / Yervoy®, pembrolizumab / Keytruda® and nivolumab / Opdivo®) have been approved for marketing, and one (atezolizumab) is undergoing regulatory review. In 2011, ipilimumab, which targets CTLA-4, became the first antibody of this class to be approved. Pembrolizumab and nivolumab, which target PD1, were subsequently granted first approvals in 2014. These drugs are currently marketed as treatments for melanoma and non-small cell lung cancer (NSCLC), but they have also undergone evaluation as treatments for other cancers, e.g., head and neck squamous cell carcinoma. A marketing application for the use of anti-PD-L1 atezolizumab as a treatment for urothelial carcinoma is undergoing a priority review by the Food and Drug Administration (FDA), and a regulatory action is expected in September 2016. An FDA action on a second application for use of atezolizumab as a treatment for NSCLC is expected in October 2016.

The biology of immune checkpoint pathways is complicated, and the use of antibodies to modulate numerous immune checkpoint targets is being explored. At least 45 antibody checkpoint modulators are currently undergoing evaluation in clinical studies of patients with a variety of cancers. In addition to CTLA-4, PD1 and PD-L1, other targets for antibodies in the clinic include B7-H3, CD70, CD40, CD137, GITR, OX40, KIR, LAG-3 and TIM3. Antibodies that modulate immune checkpoints are now ~16% of the entire clinical pipeline of antibodies for cancer, but most (~80%) are in early stage (i.e., Phase 1 or 1/2) clinical studies. First-in-human studies for over 20 antibody checkpoint modulators were initiated in 2015, and given the intense interest in the topic, many more are expected to enter clinical studies in the near future. Much work remains to be done, however, to demonstrate the relevance of some targets, and to determine suitable treatment regimens, especially when the antibody is administered as part of combination therapy.  If the potential of this class of molecules is realized, unmet medical need could be reduced, and patients’ choice of antibody therapeutics could substantially increase, in the next 5-10 years.

How long does anti-cancer antibody development take?

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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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Reslizumab: Third mAb approved in 2016

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On March 23, reslizumab (Cinqair®) became the third new monoclonal antibody product to be approved in 2016. Reslizumab targets IL-5, and it was approved by the Food and Drug Administration for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines. A marketing application for reslizumab is undergoing review by the European Medicines Agency.