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Molecules 2016, 21(12), 1741; doi:10.3390/molecules21121741

DeBouganin Diabody Fusion Protein Overcomes Drug Resistance to ADCs Comprised of Anti-Microtubule Agents

1
Viventia Bio Inc., Winnipeg, MB R3T 3Z1, Canada
2
Avipep Pty Ltd., Parkville 3052, Victoria, Australia
3
Eleven Biotherapeutics, Philadelphia, PA 19104, USA
4
Eleven Biotherapeutics, Winnipeg, MB R3E 0W3, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Els Van Damme
Received: 15 October 2016 / Revised: 9 December 2016 / Accepted: 12 December 2016 / Published: 17 December 2016
View Full-Text   |   Download PDF [1974 KB, uploaded 17 December 2016]   |  

Abstract

Antibody drug conjugates (ADC), comprised of highly potent small molecule payloads chemically conjugated to a full-length antibody, represent a growing class of therapeutic agents. The targeting of cytotoxic payloads via the specificity and selectivity of the antibody has led to substantial clinical benefits. However, ADC potency can be altered by mechanisms of resistance such as overexpression of efflux pumps or anti-apoptotic proteins. DeBouganin is a de-immunized variant of bouganin, a ribosome-inactivating protein (RIP) that blocks protein synthesis, thereby leading to apoptosis. When conjugated to trastuzumab (T-deB), deBouganin was more potent than ado-trastuzumab-emtansine (T-DM1) and unaffected by resistance mechanisms to which DM1 is susceptible. To further highlight the differentiating mechanism of action of deBouganin, HCC1419 and BT-474 tumor cells that survived T-DM1 or trastuzumab-MMAE (T-MMAE) treatment were treated with an anti-HER2 C6.5 diabody–deBouganin fusion protein or T-deB. C6.5 diabody–deBouganin and T-deB were potent against HCC1419 and BT-474 cells that were resistant to T-DM1 or T-MMAE killing. The resistant phenotype involved MDR pumps, Bcl-2 family members, and the presence of additional unknown pathways. Overall, the data suggest that deBouganin is effective against tumor cell resistance mechanisms selected in response to ADCs composed of anti-microtubule payloads. View Full-Text
Keywords: immunotoxin; deBouganin; ribosome inactivating protein; HER2; C6.5 diabody immunotoxin; deBouganin; ribosome inactivating protein; HER2; C6.5 diabody
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MDPI and ACS Style

Chooniedass, S.; Dillon, R.L.; Premsukh, A.; Hudson, P.J.; Adams, G.P.; MacDonald, G.C.; Cizeau, J. DeBouganin Diabody Fusion Protein Overcomes Drug Resistance to ADCs Comprised of Anti-Microtubule Agents. Molecules 2016, 21, 1741.

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