Home PipelineEnoblituzumab (anti-B7-H3)

Background

Enoblituzumab (also referred to as MGA271), a first-in-class monoclonal antibody created using our Fc-Optimization platform, is the leading product candidate in our B7-H3 franchise. B7-H3 is a member of the B7 family of molecules involved in immune regulation and is over-expressed on a wide variety of solid tumor types. Inhibition of certain members of the B7 family has been shown to have powerful anti-tumor effects in several solid tumor types. We designed enoblituzumab to have increased ADCC by using the same Fc Optimization that we used to create margetuximab, and to target B7-H3 that is over-expressed on tumor cells and cancer stem-like cells, as well as on the supporting tumor vasculature and underlying tissues, or stroma. Enoblituzumab is designed to target all these components of the cancer environment.

In addition to enoblituzumab, MacroGenics’ comprehensive B7-H3 franchise includes MGD009 (a Dual-Affinity Re-Targeting, or DART®, molecule targeting B7-H3 and CD3). MGD009 is in Phase 1 clinical development and employs a mechanism whereby CD3-expressing T cells are recruited to target B7-H3-expressing tumors. Finally, MacroGenics is also pursuing a pre-clinical B7-H3 antibody-drug conjugate, or ADC. (Learn More – MGD009 (B7-H3 x CD3))

Phase 1 Study Results

The ongoing Phase 1 study is being conducted to evaluate the safety of enoblituzumab in patients with advanced cancer that expresses B7-H3 in the tumor and/or tumor-associated vasculature. Additional study objectives are to define the toxicity profile, maximum tolerated dose, pharmacokinetics, immunogenicity and potential anti-tumor activity of enoblituzumab in patients with refractory cancer that expresses B7-H3.

In the dose-escalation segment of the enoblituzumab Phase 1 study, 26 patients with 15 different types of B7-H3-positive tumors were treated with increasing weekly doses ranging from 0.01 mg/kg up to 15 mg/kg. No dose-limiting toxicity was observed at doses up to 15 mg/kg, and this dose has now been used for treatment of patients in the subsequent expansion cohorts. The initial expansion cohorts (15 patients each), included patients with melanoma, prostate cancer, and a group of patients with any other B7-H3-positive tumor. Enrollment of these cohorts was completed in 2015.

In late 2014, we initiated additional dose expansion cohorts (16 patients each) using enoblituzumab as monotherapy in patients with melanoma (who have progressed despite prior checkpoint inhibitor treatment), renal cell carcinoma, triple-negative breast carcinoma, squamous cell carcinoma of the head and neck and a cohort of patients with lung or bladder carcinoma that have particularly intense expression of B7-H3. We also modified the study to dose intensify the schedule of enoblituzumab administration, and to deploy patient management and tumor assessment approaches based on “immune-related” response criteria.

Data from the ongoing Phase 1 study (as of September 21, 2015) were presented in a late-breaking abstract presentation at the 2015 Society for Immunotherapy of Cancer (SITC) Annual Meeting. Enoblituzumab was shown to be well tolerated at all dose levels tested in the Phase 1 study (up to 15 mg/kg), with Grade 3/Grade 4 drug-related adverse events (AEs) in only 4% of patients, no severe immune-related adverse events, and no drug-related treatment discontinuations. The most common AEs have been infusion-related reactions and fatigue. Mild-moderate infusion reactions have been readily managed with conventional supportive care, including administration of corticosteroids and a decreased infusion rate.

In this Phase 1 study of enoblituzumab, initial monotherapy anti-tumor activity was observed across several tumor types, including patients with prostate and bladder cancer as well as melanoma. Overall, this patient population had been heavily pre-treated (median number of prior therapies = 3), and in the patients with melanoma, all had been treated previously with one or more checkpoint inhibitors (anti-CTLA-4, anti-PD-1 and/or anti-PD-L1 antibodies).

In addition to the presentation of initial safety and activity data, findings were presented showing that increases in T-cell repertoire (TCR) clonality in the peripheral blood of tumor patients following treatment with enoblituzumab, demonstrating that enoblituzumab can modulate T cells in these patients. Collectively, these findings support the ongoing evaluation of enoblituzumab as monotherapy and in combination with other immuno-oncology agents, including pembrolizumab and ipilimumab. (Learn More – 2015 SITC Presentation)

Clinical Development

Monotherapy
MacroGenics’ Phase 1 monotherapy study of enoblituzumab is ongoing; we expect to fully enroll the additional dose expansion cohorts in 2016. As mentioned above, one of our investigators provide an update with interim data from this study in November 2015.

Combination Therapy
We are leveraging the potential power of immunotherapy combinations via the investigation of enoblituzumab in combination with checkpoint inhibitors, including ipilimumab (anti-CTLA-4) and pembrolizumab (anti-PD-1), in patients with B7-H3 positive melanoma, non-small cell lung carcinoma and head and neck cancers. The study of enoblituzumab in combination with ipilimumab began in the second quarter of 2015 and the combination with pembrolizumab began in the third quarter of 2015. (Learn More: Enoblituzumab Combination with Ipilimumab, Enoblituzumab Combination with Pembrolizumab)

Our Rights

MacroGenics retains full worldwide rights to the B7-H3 franchise (including enoblituzumab).

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