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AACR 2018: Highlighting Novel Antibody-Drug Conjugate Technologies and Immuno-Oncology

Published on 12th April

This year, the American Association for Cancer Research (AACR) will host their annual meeting April 14 – 18, 2018 in the McCormick Place North/South in Chicago, Illinois, USA.

Since the 2017 annual meeting, a dramatic wave of progress in against cancer has come to fruition and basic science findings have resulted in new drug approvals. Much has been accomplished in expanding the  use of genomic data for precision medicine and a greater focus on “big data” has helped accelerate progress in cancer research. ‘Big data’ has become crucial in helping scientists use mathematics, engineering, and artificial intelligence to diagnose cancer at an earlier stage, which helps improves outcomes.

In the last 12 months there has been a more focused and concentrated efforts to help eliminate persistent disparities – helping minorities and the medically underserved.

These developments are definitely reflected in the theme of the American Association for Cancer Research annual meeting: ‘Driving Innovative Cancer Science to Patient Care.’

The meeting is expected to draw more than 20,000 scientists, clinicians, advocates, and others to discuss advances in the field of cancer science. The multidisciplinary program will include an outstanding roster of speakers, hundreds of invited talks.

Antibody-drug Conjugates
Among the many papers and presentations, expect to find data highlights from nine presentations showcasing the Seattle Genetics’ innovative, proprietary antibody-drug conjugate or ADC platform technologies as well as its emerging immuno-oncology pipeline.

The data to be presented includes preclinical and clinical advances with brentuximab vedotin (Adcetris®; Seattle Genetics/Takeda), ladiratuzumab vedotin, SGN-CD48A and SGN-2FF as well as  the first preclinical data describing the novel empowered antibody SEA-BCMA, being developed by Seattle Genetics.

“We are an emerging multi-product company, advancing a substantial pipeline of targeted therapies for patients with solid tumors and blood cancers,” said Dennis Benjamin, Ph.D., Senior Vice President of Research at Seattle Genetics.

“New data featured in nine presentations underscore our commitment to scientific innovation and the needs of patients. These data presentations highlight the potential combination of ADCs with checkpoint inhibitors, novel ADC payloads, antibody masking technologies and progress with our immuno-oncology program, SGN-2FF. We are also presenting preclinical data for our new multiple myeloma program, SEA-BCMA, which has a phase 1 study scheduled to start this year,” Benjamin added.

Presentations
The information presented includes an oral and poster presentations on Sunday and Monday, April 15 and 16, 2018, respectively (Abstracts #930, 2803), showcasing preclinical data evaluating proprietary NAMPT inhibitors and auristatins as ADC payloads. The data show NAMPT inhibitors have a unique mechanism of action and encouraging therapeutic window. Preclinical data also describe the development of novel auristatin payloads with potential application across multiple tumor types.

An innovative approach to masking antibodies for tumor specific activation will be featured in a poster presentation on Sunday, April 15, 2018 (Abstract #250). Preclinical data demonstrate that coiled-coil masked antibodies and antibody-drug conjugates show improved tolerability and equivalent antitumor activity compared to unmasked counterparts. The data suggest this technology may be applied to a range of antibodies or ADCs and could enable their development against previously inaccessible cancer targets.

The novel preclinical program SEA-BCMA will be highlighted in a poster presentation on Tuesday, April 17, 2018 (Abstract #3833). The cell surface protein BCMA is expressed on cells of several cancer types, including multiple myeloma and other B cell malignancies. SEA-BCMA is an antibody empowered using Seattle Genetics’ proprietary Sugar Engineered Antibody (SEA) technology designed to enhance antibody effector functions. The preclinical data support initiation of a phase I trial for multiple myeloma, which is planned for 2018.

Clinical biomarker data from a phase I trial evaluating the novel immuno-oncology agent SGN-2FF in patients with advanced solid tumors will be shown in a poster presentation on Wednesday, April 18, 2018 (Abstract #5551). The preliminary data demonstrate the biological effects of SGN-2FF and support further development of this novel immuno-oncology agent.

Three poster presentations on Monday and Wednesday, April 16 and 18, 2018 (Abstracts #1789, 2742, and 5619) will highlight preclinical data evaluating the ability of brentuximab vedotin, ladiratuzumab vedotin and SGN-CD48A, each of which are auristatin-based ADCs, to elicit additional mechanisms of action, including immunogenic cell death. These data support clinical evaluation in combination with checkpoint inhibitors. Brentuximab vedotin and ladiratuzumab vedotin are being evaluated in combination with checkpoint inhibitors in multiple ongoing clinical trials.

ADC Therapeutics
Other data includes the latest updated from investigational programs highlight strong preclinical data for its two new investigational programs ADCT-601 targeting AXL and ADCT-701 targeting DLK-1 being developed by ADC Therapeutics. In addition, Jaewoong Lee, Ph.D, of The Beckman Institute of the City of Hope is expected to present the latest update on novel preclinical data for ADCT-301 targeting CD25.

“Our two new investigational programs show compelling efficacy and safety in preclinical studies,” noted Jay M. Feingold, MD, Ph.D, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics.

“These results provide an important step to advance ADCT-601 and ADCT-701 into the clinic and enlarge our pipeline of PBD-based ADCs in multiple ongoing clinical trials for the treatment of both solid and hematological cancers,” Feingold added.

Presentations
Presentations include updated about ADCT-701, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting DLK1-expressing tumors. (Abstract #744, April 15, 1:00 pm – 5:00 pm CT). The ADC is site-specifically conjugated using GlycoConnect™ technology to PL1601, which contains a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199. The investigational agent has demonstrated potent and specific in vitro and in vivo anti-tumor activity in DLK1-expressing cancer-derived models and it was stable and well tolerated in rats.

Another updated includes the latest update of the preclinical activity of ADCT-601, a novel pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) targeting AXL-expressing tumors (Abstract #2792A, April 16, 1:00 pm – 5:00 pm CT). ADCT-601 is an ADC composed of a humanized IgG1 antibody against human AXL, site-specifically conjugated using GlycoConnect™ technology to PL1601, which contains a valine-alanine cleavable linker and the PBD dimer cytotoxin SG3199. The investigational agent has demonstrated potent and specific in vitro and in vivo anti-tumor activity in various cancer-derived models with different levels of membranous AXL, and it was stable and well tolerated in rats.

CD25 enables oncogenic BCR- and TCR-signaling and represents a therapeutic target in lymphoblastic malignancies (Abstract #2983, April 16, 2018, 4:05 PM – 4:20 PM). Novel data identifies CD25 as a previously unrecognized feedback regulator of oncogenic B/TCR-signaling supporting CD25 as a therapeutic target in refractory lymphoid malignancies. ADC Therapeutics’ ADCT-301 has demonstrated durable remissions in patient-derived Ph+ ALL cells PDX models

Eleven Biotherapeutics
Eleven Biotherapeutics, a late-stage clinical company developing next-generation antibody-drug conjugate therapies is expected to present preclinical data from the company’s novel, next-generation ADC program using an innovative deBouganin cytotoxic protein payload.

“We have uniquely designed our deBouganin payload to address tumor indications that can only be reached through systemic delivery. Our data show that deBouganin exhibits certain advantages over first-generation ADCs, which use more conventional small molecule cytotoxins, with respect to cell killing power, including the ability to kill cancer stem cells, circumvent multi-drug resistance and avoid cross-resistance mechanisms,” said Gregory P. Adams, Ph.D., Chief Scientific Officer of Eleven Biotherapeutics.

“We are pleased to be presenting these promising data highlighting the potential activity and differentiation of our approach compared to first-generation ADCs,” he added.

Presentations
DeBouganin is a proprietary de-immunized variant of bouganin, a ribosome inactivating protein that when internalized blocks protein synthesis, thereby leading to cell death. Eleven Biotherapeutics will present data from its VB6-845d program, a next-generation ADC comprised of a Fab fragment specific for the epithelial cell adhesion molecule (EpCAM) genetically linked to deBouganin via a furin protease sensitive peptide. Data being presented suggest that VB6-845d mediates tumor cell killing by an immunogenic cell death (ICD) pathway. The potential cross-priming effect initiated by VB6-845d-induced ICD suggests that VB6-845d in combination with immune checkpoint inhibitors may enhance their effectiveness in EpCAM-positive epithelial cancers. Poster presentation: VB6-845d Tumor Cell Killing Elicits Biologic Features of Immunogenic Cell Death (Date and Time: April 16, 2018 from 1:00 to 5:00 p.m. CT)

Targeted protein therapeutics or TPTs are single-protein therapeutics composed of targeting moieties genetically fused via peptide linker to cytotoxic protein payloads. TPTs are designed to overcome efficacy and safety challenges inherent within ADCs. Poster presentation: Engineering and Characterization of Anti-PSMA Humabody-DeBouganin Fusion Proteins (April 18, 2018 from 8:00 a.m. to 12:00 p.m. CT).


Last Editorial Review: April 12, 2018

Featured Image: New Orleans, LA – The AACR 2016 Annual Meeting. Courtesy: © AACR/Scott Morgan. Used with permission.

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