Home PipelineFlotetuzumab (CD123 x CD3)

Background

Flotetuzumab (also known as S80880) is a humanized DART® molecule that recognizes both CD123 and CD3. CD123, the Interleukin-3 receptor alpha chain, has been reported to be over-expressed on cancer cells in a wide range of hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). AML and MDS are thought to arise in and be perpetuated by a small population of leukemic stem cells (LSCs) that generally resist conventional chemotherapeutic agents. LSCs are characterized by high levels of CD123 expression that is low or absent in the corresponding hematopoietic progenitors and stem cell populations in normal human bone marrow.

Flotetuzumab was designed to redirect T lymphocytes to kill CD123-expressing cells. To achieve this, the DART molecule combines a portion of an antibody recognizing CD3, an activating molecule expressed by T cells, with an arm that recognizes CD123 on the target cancer cells. Flotetuzumab is currently being evaluated in a Phase 1 dose expansion study.

Clinical Development

An ongoing Phase 1, first-in-human study of flotetuzumab is being conducted to determine safety, tolerability, maximum tolerated dose and initial anti-leukemic activity in patients with relapsed or refractory AML or intermediate-2/high risk MDS. Updated data was presented at an oral session at the ASH Annual Meeting in December 2017. At the time, a total of 57 patients had been enrolled, including 11 AML patients in the dose expansion cohort.

Consistent with the dose escalation data that had previously been presented at ESMO Congress 2017 in September, flotetuzumab continued to demonstrate acceptable tolerability in patients treated in the dose expansion cohort. Infusion-related reaction and cytokine release syndrome (CRS) were the most common adverse events observed, with Grade 3 CRS occurring in 9 of 57 patients (15.8%). Implementation of a two-step, lead-in dose as well as early intervention with anti-cytokine therapy helped to limit the severity and incidence of CRS.

As of the data cut-off date, of the eight evaluable patients in the dose expansion cohort who received a lead-in dose followed by 500 ng/kg/day of flotetuzumab via continuous IV infusion, six patients (75%) had evidence of anti-leukemic activity, with three of these patients experiencing an objective response. This included two patients who experienced CR/CRi and one patient who achieved MLF (morphologic leukemia-free state).

The duration of response for the eight patients who achieved a MLF, CRi or CR in the dose escalation and dose expansion cohorts ranged from 1.0 to 5.8 months, with five of these responses ongoing as of the November 30, 2017 data cut-off. (Learn More: ASH 2017 Oral Presentation).

Further, in a translational data poster presentation at ASH 2017, MacroGenics described studies that support a rationale for using checkpoint blockade as an approach to potentially enhance the anti-leukemic activity of flotetuzumab. Among these findings, modulation of the PD-1/PD-L1 pathway was observed in patients treated with flotetuzumab, and the combination of flotetuzumab and PD-1/PD-L1 inhibitors was shown to synergistically enhance T-cell mediated cytotoxicity against AML cell lines in vitro. (Learn More: ASH 2017 Rational for Combining with Anti-PD-1).

Pre-Clinical Development

In November 2013, one of our academic investigators presented data from a pre-clinical study of flotetuzumab at the 2013 ASH Annual Meeting. The pre-clinical data highlighted the ability of flotetuzumab to redirect T cells against CD123-positive AML blasts. (Learn More: 2013 ASH Presentation).

In May 2015, a nonclinical research paper on flotetuzumab was published in Science Translational Medicine. This published research shows anticancer activity in vitro and in mouse models together with favorable pharmacodynamic and safety profile in nonhuman primates. In this paper, MacroGenics’ scientists demonstrated that flotetuzumab can arm T cells from AML patients to reduce blast counts in vitro and is effective in eliminating AML cells implanted in mice in the presence of human effector cells. Furthermore, flotetuzumab administered to cynomolgus monkeys demonstrated potent pharmacodynamic activity in the form of near complete elimination of circulating CD123-positive cells at doses that were safe and well tolerated.

Our Rights

Under the terms of a collaboration, MacroGenics retains full development and commercialization rights to flotetuzumab in the U.S., Canada, Mexico, Japan, South Korea and India. MacroGenics’ partner, Servier, has rights to flotetuzumab in all other countries. (Learn More: Servier DART Collaboration)

Learn More:

Please note – you will leave a website owned by MacroGenics, Inc.

MacroGenics is not responsible for any content on the third party website.

Ok Close