During the upcoming 35th annual meeting of the Society for Immunotherapy of Cancer’s (SITC) being held November 9-14, 2020, Seagen (previously known as Seattle Genetics) will highlight the latest updated immuno-oncology data from its broad pipeline of therapies of antibody-drug conjugates and the company’s emerging sugar-engineered antibodies.

The company will present six abstracts demonstrating the continued progress in advancing innovative research and late-stage antibody-drug conjugates and innovative empowered antibody pipeline utilizing its proprietary sugar-engineering antibody (SEA) technology.

Vedotin-based ADCs
Auristatins (including monomethyl auristatin E; MMAE; vedotin) -based ADCs are designed to drive cytotoxicity in tumor cells by engaging tumor antigens on the cell surface, internalizing with the cell surface antigen, and delivering an MMAE payload. These tubulin-binding agents release the active payload after internalization and processing within endosomes or lysosomes. [1]

After intracellular delivery, MMAE induces mitotic arrest, as well as an endoplasmic reticulum (ER) stress response which occurs when proteins are not properly folded or conformed (misfolded protein). ER stress interferes with normal physiological functions of the cell which results from microtubule disruption.

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Data presented at SITC will highlight how Seagen’s distinct valine-citrulline-MMAE (vedotin)-based ADCs induce immunogenic cell death (ICD) by activating the innate immune cells and changing the tumor microenvironment to a more inflammatory state thereby enhancing the efficacy of other cancer immunotherapies. The presentations also demonstrate the ability of MMAE to induce the hallmarks of ICD in multiple cancers across different tissue origins. These findings will be presented for tisotumab vedotin, ladiratuzumab vedotin (SGN-LIV1A) and across vedotin-based ADCs (Abstracts #617, #618 and #323).

Tisotumab vedotin
Tisotumab vedotin is an investigational antibody-drug conjugate (ADC) composed of a human antibody targeted to tissue factor (TF), a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. The investigational agent is being developed by Seagen and Genmab.

Ladiratuzumab vedotin
Ladiratuzumab vedotin is an investigational antibody-drug conjugate or ADC designed to deliver a potent and clinically validated cell-killing, microtubule-disrupting, agent, called monomethyl auristatin E (MMAE) via a protease-cleavable linker, to cancer cells which express the protein LIV-1. This protein, expressed by most metastatic breast cancers, is also detected on multiple solid tumors including prostate, melanoma, ovarian, uterine, and cervical cancers.

“Our vedotin-based ADC research at SITC illustrates the impact of immunogenic cell death (ICD) on the tumor microenvironment,” said Roger Dansey, M.D., Chief Medical Officer at Seagen.[1]

“Importantly, these data support the mechanistic rationale for combining vedotin-based ADCs with immuno-oncology therapies in the clinic,” Dansey added.

Sugar-engineering antibody technology
The presented data also includes Seagen’s novel proprietary sugar-engineerd antibody (SEA) technology, which produces nonfucosylated antibodies that uniquely enhance activity targeting key immune-modulating receptors.

Seagen’s SEA technology is a novel approach that may improve the immune response to cancer cells. By growing antibody-producing cells in the presence of the 2-fluorofucose sugar, scientists are able to block the cellular fucosylation pathway. This creates afucosylated antibodies that can bind more tightly to an activating receptor on innate immune cells increasing receptor cross-linking and improving antibody-dependent cellular cytotoxicity (ADCC), an important antitumor immune response. [2][3]

During the SITC preclinical data will be presented from SEA-TGT (Abstract #250), a novel investigational nonfucosylated human IgG1 TIGIT antibody. SEA-TGT is in an ongoing phase I clinical trial for patients with solid tumors and lymphoma (NCT04254107).

In addition, preclinical data will be presented for SEA-CD40 (Abstract #438), a novel investigational, nonfucosylated human IgG1 antibody targeted to CD40, an immune stimulatory receptor found on antigen-presenting cells. SEA-CD40 is in a phase 1 trial for pancreatic cancer in combination with chemotherapy and a PD-1 inhibitor (NCT02376699).

“We believe our immuno-oncology candidates have a best-in-class potential, creating a strong foundation for our immunotherapy pipeline,” said Scott Peterson, Ph.D., Senior Vice President of Research at Seagen.

“Data presented at SITC demonstrate that our sugar-engineered antibodies are differentiated and have the potential to improve efficacy and address unmet needs in cancer,” Peterson added.

Data for brentuximab vedotin (Adcetris®) presented during the meeting demonstrates its ability to selectively target and kill CD30-positive T regulatory cells (Tregs) that contribute to resistance to cancer immunotherapies (Abstract #696). This presented data supports that brentuximab vedotin may have an immunomodulatory effect through selective depletion of highly active Tregs.

250SEA-TGT is a nonfucosylated antibody with distinct and amplified effector function activity that leverages the dependencies of anti-TIGIT anti-tumor activity upon FcγR engagement Alyson J. Smith, PhD; Weiping Zeng; William Siegall; Bryan Grogan; Jane Haass; Amber Blackmarr; Robert Thurman; Scott Peterson; Shyra J. Gardai, PhD;

E-Poster /

November 11-14

323Systemic administration of ladiratuzumab vedotin alone or in combination with pembrolizumab results in significant immune activation in the tumor microenvironment in metastatic breast cancer patients Lajos Pusztai, MD; Hailing Lu, MD, PhD; Christopher Hale, PhD; Anne Grosse-Wilde, PhD; Jennifer Specht, MD; Shanu Modi, MD; Hyo Han, MD; Javier Cortes, MD PhD; Mafalda Oliveira, MD, PhD; Phillip Garfin, MD, PhD; Zejing Wang, MD, PhD; Matthew Onsum, PhD;

E-Poster /

November 11-14

438Synergy between SEA-CD40 and chemotherapeutics drives curative anti-tumor activity in pre-clinical models Weiping Zeng; Haley Neff-LaFord; Sahar Ansari; Celine Jacquemont, PhD; Michael Schmitt, MD, PhD; Shyra J. Gardai, PhD;

E-Poster /

November 11-14

617Tisotumab vedotin shows immunomodulatory activity through induction of immunogenic cell death Elizabeth Gray, PhD; Kelly Hensley; Sean Allred; Esther Trueblood; John Gosink; Robert Thurman; Kaleb Smith; Celine Jacquemont, PhD; Mark Bieda; Jason Gow; Jeffrey R. Harris; Lauren K. Brady; Ibrahima Soumaoro; Shweta Jain; Leonardo Nicacio; Shyra J. Gardai, PhD;

E-Poster /

November 11-14

618Vedotin ADCs induce ER stress and elicit hallmarks of ICD across multiple cancer indicationsKerry Klussman, B.S.; Elena-Marie Tenn; Shaylin Higgins; Rebecca Mazahreh; Katie Snead; Joseph Z. Hamilton; Bryan M. Grogan, MS; Johann Sigurjonsson; Anthony Cao; Shyra J. Gardai, PhD; Bernard A. Liu;

E-Poster /

November 11-14

696Brentuximab vedotin, a CD30 targeting antibody-drug conjugate, selectively depletes activated Tregs in vitro and in vivoBryan M. Grogan, MS; Reice D. James, BS; Michelle Ulrich, BS; Shyra J. Gardai, PhD; Ryan Heiser, PhD;

E-Poster /

November 11-14

Clinical trial
A Safety Study of SGN-TGT (SEA-TGT) in Patients With Advanced Cancer – NCT04254107

Highlights of prescribing information
Brentuximab vedotin (Adcetris®; Seagen/Takeda) [Prescribing Information]

[1] Klussman K, Tenn E, Higgins S, et al. Vedotin ADCs induce ER stress and elicit hallmarks of ICD across multiple cancer indications. (618). Journal for ImmunoTherapy of Cancer 2020;8:doi: 10.1136/jitc-2020-SITC2020.0618
[2] Okeley NM, Alley SC, Anderson ME, et al. Development of orally active inhibitors of protein and cellular fucosylation. Proc Natl Acad Sci U S A. 2013;110(14):5404-5409.
[3] Field JJ, Okeley NM, Zeng W, et al. Understanding the mechanism of 2FF-induced immune modulation [abstract]. Proc Am Assoc Cancer Res. 2016;76(14 Suppl):Abstract 4005.

Featured image: 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer’s (SITC), held November 6–10, 2019, in National Harbor Md. Photo courtesy: © 2019 Society for Immunotherapy of Cancer’s (SITC). Used with permission.

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