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AACR 2017: Advancing Antibody-Drug Conjugate and Novel Immuno-Oncology

Published on 05th April

Multiple data presentations supporting Seattle Genetics’ advancing antibody-drug conjugate or ADC and immuno-oncology programs were presented at the Annual Meeting of the American Association for Cancer Research (AACR), being held April 1-5, 2017, in Washington, D.C.

Commenting on the number of these presentations, Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development, at Seattle Genetics, noted: “Our expertise in empowered-antibody innovation drives a substantial, advancing pipeline of more than a dozen clinical and preclinical programs, both ADCs and immuno-oncology agents.”

“Preclinical data presented at AACR support multiple ongoing clinical studies evaluating combination treatment of brentuximab vedotin and nivolumab (Opdivo®; Bristol-Myers Squibb Company) in relapsed Hodgkin and non-Hodgkin lymphoma and phase I trials of two proprietary immuno-oncology agents, SEA-CD40 and SGN-2FF, in solid tumors.

Drachman also said that “Seattle Genetics is transforming into a global, multi-product oncology company through dedication to scientific innovation and the needs of patients.”

Analysis
One of the presentations highlighted the clinical biomarker analyses of CD33 targeting vadastuximab talirine (SGN-CD33A; 33A), an ADC being broadly evaluated across multiple lines of therapy in patients with myeloid malignancies, including the ongoing global phase III CASCADE trial in newly diagnosed, older AML patients and phase I/II trial in patients with newly diagnosed myelodysplastic syndrome (MDS).

An analysis from a phase I monotherapy study in AML was presented in a poster presentation on Tuesday, April 4, 2017 (Abstract #CT120).

Immuno-Oncology
Researchers at Seattle Genetics are presenting preclinical data feature SEA-CD40 and SGN-2FF,  two immuno-oncology agents which are both in phase I clinical trials.

SEA-CD40, an innovative immuno-oncology agent, is one of Seattle Genetics non-ADC programs and uses a novel sugar-engineered antibody (SEA) technology to produce a non-fucosylated antibody targeting CD40.  The approach is designed to empowering antibodies and is considered complementary to the company’s ADC technology. It builds on our extensive experience targeting CD40, an immune-activating receptor capable of driving an anti-tumor response.  Data from pre-clinical studies, presented in a poster on Tuesday, April 4, 2017 (Abstract #3647), suggests that the investigational compound SEA-CD40 may be o able to stimulate a patient’s own immune system to fight their cancer.

In the poster presentation, the researchers showed that treatment of CD-40 transgenic mice with SEA-CD40 resulted in cytokine induction and B-cell depletion.

The pre-clinical data focuses on the mechanism of action through activation of anti-tumor immune response and potential for combination with checkpoint inhibitors. SEA-CD40 targets the protein CD40 using Seattle Genetics’ proprietary sugar-engineered antibody (SEA) technology to produce a non-fucosylated antibody.[1]

SEA-CD40 is currently under investigation in a phase I trial in metastatic or unresectable solid tumors and hematologic malignancies.

SEA-2FF
This year Seattle Genetics also presented pre-clinical data on a novel small molecule, 2-fluorofucose (SEA-2FF).  This investigational compound blocks cellular incorporation of a sugar (fucose) whish is shown to have anti-tumor activity by two distinct mechanisms. The inhibition of fucosylation of proteins is intended to stimulate the immune system and slow the growth and spread of cancer cells.

Pre-clincal data demonstrates that SEA-2FF, as a single oral agent, delays the growth of solid tumors in multiple xenograft models.  But SEA-2FF also enhances the antibody-mediated immune response to cancers using a tumor vaccine model.

Furthermore, ongoing phase I study of SGN-2FF in patients with relapsed or refractory (advanced) solid tumors, including non-small cell lung cancer, were highlighted in an oral presentation during the New Drugs on the Horizon symposium on Sunday, April 2, 2017 (Session #DDT02-02).

Combination treatment
During this year’s annual meeting, Seattle Genetics and Unum Therapeutics presented pre-clinical data evaluating combination treatment with Antibody-Coupled T cell Receptor (ACTR) engineered autologous T cells and an antibody targeting B-cell maturation antigen or BCMA.

The ACTR technology enables the programming of a patient’s immune system to attack tumor cells when co-administered with tumor-specific therapeutic antibodies.  The pre-clinical data support clinical evaluation of a humanized non-fucosylated anti-BCMA antibody, known as SEA-BCMA, being developed using Seattle Genetics’ novel sugar-engineered antibody (SEA) technology, and ACTR T cell combination treatment in multiple myeloma patients.

Designed to engage the Fc domain of therapeutic antibodies, the ACTR technology, is a universal, engineered T cell therapy consisting of the extracellular domain of human CD16 and the intracellular T cell co-stimulatory and signal domain.

One presentation highlighted data from pre-clincal studies on targeting BCMA-positive multiple myeloma cells with ACTR in combination with SEA-BCMA.[2] In this poster (abstract #4605), Tooba Cheema, Ph.D, a senior scientist at Unum Therapeutics, explained that the cell surface protein BCMA, which recently has emerged as an attractive  therapeutic target in multiple myeloma, is expressed on cells of several cancer types, including multiple myeloma and other B cell malignancies. Cheema confirmed that BCMA expression is restricted expression on plasma cells with little to no expression on other, normal, cell, but is upregulated on the surface of specific cancer cells.

A number of different approches designed to target BCMA are currently under way, including chimeric antigent receptor (CAR) T-cell therapies, bispecific antibodies and ADCs.

One of these approaches involves a humanized afucosylated anti-BCMA antibody, SEA-BCMA, which binds to antibody-coupled T cell receptor (ACTR) expressing T cells with high affinity and mediates T cell activation, potent cytotoxicity, cytokine release and proliferation across a wide range of BCMA-expressing multiple myeloma cells.

In preclinical studies, the researchers noted ACTR activity specific to SEA-BCMA.  They also noted no activity on BCMA negative tumor lines. Based on these studies, they believe SEA-BCMA may offer a valid option for the treatment of patients with multiple myeloma.

Immunogenic cell death
A presentation describing the ability of brentuximab vedotin (Adcetris®) to activate antitumor immune responses, supports continued clinical evaluation of the agent in combination with checkpoint inhibitors.

An evaluation of the preclinical data confirmed the ability of brentuximab vedotin to induce immunogenic cell death was be presented in a poster presentation on Wednesday, April 5, 2017 (Abstract #5588). These data demonstrate that brentuximab vedotin-treated tumor cells initiate an anti-tumor immune response alone and, to a greater extent, in combination with anti-PD-1 agents, and support combination strategies with immuno-oncology regimens, such as the ongoing phase I/II/ clinical trials evaluating brentuximab vedotin and nivolumab in relapsed Hodgkin and non-Hodgkin lymphoma.


Last Editorial Review: April 5, 2017

Featured Image: United States Capitol Building, Washington, DC, capital of the United States of America Courtesy: © 2017 Fotolia. Used with permission.

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