Background SGN-B6A is a novel investigational antibody-drug conjugate (ADC) directed to integrin beta-6 and uses the clinically validated vedotin drug-linker platform that delivers the microtubule disrupting agent, monomethyl auristatin E (MMAE).1 SGN-B6A is designed to bind and internalize the integrin beta-6/ADC complex from the surface of malignant cells and release the cytotoxic payload MMAE. We have previously demonstrated the antitumor activity of SGN-B6A in cell line-derived xenograft models originating from multiple carcinomas as well as patient-derived xenograft models of non-small cell lung cancer (NSCLC).² Other ADCs delivering the MMAE payload (including vedotin ADCs using the antibodies brentuximab, enfortumab, ladiratuzumab, and tisotumab) have been shown to induce immunogenic cell death (ICD) in preclinical models^3-7 and have demonstrated promising clinical activity in combination with immunotherapy.^8-10 Since the induction of ICD appeared to be a consequence of the activity of MMAE, and is independent of the antibody that delivers it, we hypothesized that this mechanism of action may also apply to SGN-B6A.

Methods In vitro and in vivo assessment of ICD was performed in cell lines derived from pancreatic carcinoma. Induction of ICD markers were assessed using plate-based assays, flow cytometry, and immunoblotting. ICD was also assessed in vivo using RNA sequencing and immunohistochemistry (IHC) on cell line-derived xenografts.

Results Consistent with this hypothesis we observed that tumor cells treated with SGN-B6A in vitro showed key hallmarks of immunogenic cell death, including markers of endoplasmic reticulum (ER) stress, exposure of calreticulin, and release of ATP and high mobility group protein B1 (HMGB1). Further, in vivo studies demonstrated that treatment with SGN-B6A led to immune activation and recruitment of immune cells to the tumor environment.

Conclusions Preclinical models suggest that, like other vedotin ADCs, SGN-B6A induces immunogenic cell death which then promotes activation and recruitment of immune cells to the tumor. These data provide a strong rationale for the combination of SGN-B6A with immunotherapies, which may further lead to enhanced antitumor activity and can be utilized as a potential treatment for integrin-beta-6-expressing tumors including NSCLC, head and neck squamous cell carcinoma, and esophageal carcinoma. Altogether, our preclinical results support the current evaluation of SGN-B6A in an ongoing phase 1 study (NCT04389632).

References

1. Lyon RP, Schmitt MW, Jonas M, et al. SGN-B6A: A new MMAE ADC targeting integrin beta-6 in multiple carcinoma indications [abstract]. Cancer Res 2020;80(Suppl 16):Abstract 2906.

2. Lyon RP, Gosink JJ, Hale CS, et al. Activity of SGN-B6A in patient-derived xenograft models of non-small cell lung cancer [abstract]. Cancer Res 2021;81(Suppl 13): Abstract 914.

3. Cao AT, Law CL, Gardai SJ, et al. Auristatin-based Antibody Drug Conjugates Activate Multiple ER Stress Response Pathways Resulting in Immunogenic Cell Death and Amplified T-cell Responses [abstract]. Cancer Res 2016;76(Suppl 14): Abstract 4914.

4. Cao AT, Law CL, Gardai SJ, et al. Brentuximab vedotin-driven immunogenic cell death enhances antitumor immune responses, and is potentiated by PD1 Inhibition in vivo [abstract]. Cancer Res. 2017;77(Suppl 13):Abstract 5588.

5. Cao AT, Law CL, Gardai SJ, et al. Additional mechanisms of action of ladiratuzumab vedotin contribute to increased immune cell activation within the tumor [abstract]. Cancer Res 2018;78 (Suppl 13):Abstract 2742.

6. Liu BA, Olson D, Snead K, et al. Enfortumab vedotin, an Anti-Nectin-4 ADC demonstrates bystander cell killing and immunogenic cell death anti-tumor activity mechanisms of action in urothelial cancers [abstract]. Cancer Res 2020;90(Suppl 16): Abstract 5581.

7. Gray E, Hensley K, Allred, S, et al. Tisotumab vedotin shows immunomodulatory activity through induction of immunogenic cell death [abstract]. J Immunother Cancer 2020;8(Suppl 3):Abstract 653.

8. Pusztai L, Lu H, Hale C, et al. Systemic administration of ladiratuzumab vedotin alone or in combination with pembrolizumab results in significant immune activation in the tumor microenvironment in metastatic breast cancer patients [abstract]. J Immunother Cancer 2020; 8 (Suppl 3): Abstract 349.

9. Rosenberg JE, Flaig TW, Friedlander TW, et al. Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma [abstract]. J Clin Onc 2020;38(Suppl 6): 441.

10. Herrera, AF, Moskowitz, AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 2018;131(11):1183–1194.

Ethics Approval All animal studies were conducted in accordance with protocols reviewed and approved by the Institutional Animal Care and Use Committee at Seagen or the external testing facility that conducted the studies.