Featured Image: General views at the American Society for Clinical Oncology (ASCO) annual meeting. Courtesy: © ASCO/Max Gersh 2015. Used with permission.
Featured Image: General views at the American Society for Clinical Oncology (ASCO) annual meeting. Courtesy: © ASCO/Max Gersh 2015. Used with permission.

Chemotherapy remains the standard of care in the treatment of many types of cancer. However, one of the problems with chemotherapeutics is that it damages – and kills – not only cancer cells but also healthy ones.

In a pursuit to develop more targeted therapies, scientists at AbbVie and their partners at Seattle Genetics and other companies are working on novel therapies, including antibody-drug conjugates, designed to target cancer and reduce the impact of chemotherapy on healthy cells.  In addition, ADCs are also expected to reduce the amount of cytotoxic, anticancer drug needed for treatment.

But what’s more, based on the company’s dual variable domain (DVD) antibody technology, scientists at AbbVie are also investigating the potential to develop ADCs that can target two proteins at once.

MabPlex
 

ASCO 2016
Scientists from Abbvie will present data from multiple clinical trials evaluating the company’s portfolio of investigational oncology medicines during the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO), June 3-7, 2016 in Chicago.

Notably, researchers will present data from studies evaluating the efficacy of ABT-414 as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (GBM), [1] an aggressive malignant primary brain tumor.[2]   (van den Bent et al.; Abstract 2542; Poster Session; Sunday, June 5, 2016; 8-11:30 a.m. CDT)

ABT-414 is an investigational ADC targeting EGFR developed by AbbVie researchers with components in-licensed from Life Science Pharmaceuticals and Seattle Genetics.[1]  In 2014, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency granted orphan drug designation for the treatment of glioblastoma and glioma, respectively.[3][4]

During ASCO data data will also be presented from a  phase I, open-label, dose-escalation and expansion study of ABBV-399, an investigational ADC targeting c-Met, in patients with advanced solid tumors (Strickler et al.; Abstract 2510; Poster Session; Sunday, June 5, 2016; 8-11:30 a.m. CDT with Poster Discussion Sunday, June 5, 2016; 11:30 a.m.-12:45 p.m. CDT).[5]

Commenting on the large number of oral and poster presentations to be presented during ASCO, Michael Severino, MD, executive vice president of research and development and chief scientific officer, of AbbVie noted: “The multiple data presentations … underscore [our] commitment to pursue new cancer therapy options, with the potential to make a real and remarkable impact on the lives of people affected by cancer.”

“[We’re] committed to working together with the oncology research community, healthcare and clinical experts, industry peers, patients and patient advocacy groups, to discover and develop therapies with the goal of transforming the treatment of cancer,” Severino concluded.

Improving outcomes
Over the last years, Abbvie has demonstrated that a desire to develop medicines that make a transformational improvement in cancer treatment and outcomes for cancer patients.  This drive was again emphasized in April when the company announced that it had entered into a collaboration with CytomX Therapeutics to co-develop and co-commercialize Probody™ Drug Conjugates against CD71, also known as transferrin receptor 1 (TfR1) and stated it has acquired Stemcentrx, the developer of  a late-stage antibody-drug conjugate, rovalpituzumab tesirine (Rova-T; S16LD6.5) currently in registrational trials for small cell lung cancer (SCLC).

Probody therapeutics
CD71, the target of CytomX’ Probody™ Drug Conjugates,  is highly expressed in a number of solid and hematologic cancers and has attractive molecular properties for efficient delivery of cytotoxic payloads to tumor cells. Probody therapeutics are designed to take advantage of unique conditions in the tumor microenvironment to enhance the tumor-targeting features of an antibody and reduce drug activity in healthy tissues.

Rovalpituzumab tesirine
Rovalpituzumab tesirine  is a novel biomarker-specific therapy that is derived from cancer stem cells and targets delta-like protein 3 (DLL3) that is expressed in more than 80% of SCLC patient tumors and is not present in healthy tissue. The investigational drug combines a targeted antibody that delivers a cytotoxic agent directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.

In Phase I/II studies of relapsed SCLC patients who have previously failed one or more standard therapies, rovalpituzumab tesirine demonstrated overall response rates of 44% in the patients identified with high expression of DLL3. The expression of DLL3 suggests rovalpituzumab tesirine may also be useful across multiple tumor types, including metastatic melanoma, glioblastoma multiforme, prostate, pancreatic and colorectal cancers, where DLL3 expression ranges from 50-80%.

“[Rovalpituzumab tesirine] is the first predictive biomarker-based therapy associated with drug efficacy in small cell lung cancer, ” said Charles Rudin, M.D., Ph.D., chief, thoracic oncology service, Memorial Sloan Kettering Cancer Center. “And that is a big deal for this difficult disease,” he concluded.

Phase I 
During the meeting of the European Cancer Congress in Vienna, Austria, in September 2015, results from a phase I trial with rovalpituzumab tesirine in 79 patients with SCLC who had progressed after first line or second line therapy were presented.

“While other cancers have multiple treatment options, there is only one agent approved in SCLC, and none available in the third line setting; the outlook for these patients is dismal,” M. Catherine Pietanza, MD, an Assistant Attending Physician at the Memorial Sloan Kettering Cancer Center, New York, noted.

Third line therapy is given after first and second line treatments have failed to halt the progression of disease.

In this trial, the patients ranged in age from 44-81, with a median age of 62 years. As is normal in phase I trials, they received escalating doses of rovalpituzumab tesirine once every three weeks until toxicity reached a point at which the increase in dose needed to be stopped.

“Of the 48 tumor samples we were able to analyse, 33 were positive for DLL3. Among the 29 DLL3+ patients we could treat at the maximum tolerated dose of rovalpituzumab tesirine, ten (34%) had a partial response and nine (31%) had disease stabilisation. The duration of response among these patients was more than 178 days, with no cases of disease progression,” Pietanza explained.

During the upcoming annual meeting of updated trial data of rovalpituzumab tesirine will be presented (Rudin et al.; Late Breaking Abstract 8505; Oral Abstract Session; Sunday, June 5, 2016; 9:44-9:56 a.m. CDT and Peng et al; Abstract 11611; Poster Session; Monday, June 6, 2016; 1:00 – 4.30).

Beyond rovalpituzumab tesirine
Beyond rovalpituzumab tesirine, Stemcentrx, now part of AbbVie, has four novel compounds in clinical trials, including antibody-drug conjugates.  These novel compounds include new treatments across several solid tumor indications, including triple-negative breast cancer, ovarian cancer and non-small cell lung cancer. The company has additional pre-clinical compounds advancing toward clinical trials in 2016 and a proprietary technology platform that leverages stem cell biology to identify and screen potential targets against live tumor tissue to more predictably advance discovery and development of new assets.

By exploring and investing in new pathways, technologies and approaches, the scientists at AbbVie are breaking ground in some of the most widespread and difficult-to-treat cancers.

For a complete overview of oral and poster presentation covering antibody-drug conjugates, click here.