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618 Vedotin ADCs induce ER stress and elicit hallmarks of ICD across multiple cancer indications
  1. Kerry Klussman1,
  2. Elena-Marie Tenn1,
  3. Shaylin Higgins1,
  4. Rebecca Mazahreh1,
  5. Katie Snead1,
  6. Joseph Hamilton1,
  7. Bryan Grogan1,
  8. Johann Sigurjonsson1,
  9. Anthony Cao2,
  10. Shyra Gardai1 and
  11. Bernard Liu1
  1. 1Seattle Genetics, Inc., Bothell, WA, USA
  2. 2Celgene/Bristol-Myers Squibb, San Francisco, CA, USA


Background Effective cancer treatment requires durable elimination of malignant cells. Cytotoxic chemotherapeutic agents used to treat cancer often show initial anti-tumor efficacy, but fail to produce long-term durable responses in patients. The elicitation of durable responses and improved survival in response to cytotoxic agents may be associated with the induction of innate and adaptive immune response to the cancer. For example, tumor cells undergoing apoptosis following exposure to some cytotoxic agents emit immunostimulatory damage-associated molecular patterns (DAMPs), this form of cell death is termed immunogenic cell death (ICD). ICD can promote the recruitment and activation of both the innate and adaptive immune system, providing an additional mechanism to drive an anti-tumor response.

Methods Vedotin-based antibody drug conjugates (ADCs) drive cytotoxicity in tumor cells by engaging tumor antigens on the cell surface, internalizing with the cell surface antigen, and delivering monomethyl auristatin E (MMAE) payload. Following intracellular delivery, MMAE induces mitotic arrest, as well as an endoplasmic reticulum (ER) stress response resulting from microtubule disruption. Following tumor cell treatment, indicators of the ER stress response are observed with vedotin-based ADCs including induction of phospho-JNK and CHOP, This mechanism of MMAE induced ER stress results in emission of hallmark ICD DAMPs including cell-surface calreticulin, extracellular release of HMGB1 and ATP. In this presentation we highlight the ability of MMAE to induce the hallmarks of ICD in multiple cancers across different tissue origins using distinct valine-citrulline-MMAE (vedotin)-based ADCs.

Results The culmination of these ICD hallmarks resulted in innate immune cell activation in vitro and in vivo in mouse xenograft models. Tumor bearing mice treated with vedotin-based ADCs resulted in the promotion of immune cell recruitment and activation in tumors. Analysis of immune activation by vedotin-based ADCs included production of innate cytokines and upregulation of HLA/MHC-Class I/II expression, which supports a role in activating both the innate and adaptive immune response. To further our understanding of the potent and broad ability of vedotin ADCs to induce ICD, we have also begun to examine the ICD potential of different classes of ADC payloads including other microtubule inhibitors (auristatins and maytansines), and DNA damaging agents (DNA alkylators or topoisomerase inhibitors). Initial data indicate differences in ICD induction by these agents.

Conclusions These results help build the rationale for vedotin-based ADCs as preferred partners for immune checkpoint blockade agents.

Ethics Approval Studies with human samples were performed according to institutional ethics standards. Animal studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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