title: DeBouganin Diabody Fusion Protein Overcomes Drug Resistance to ADCs Comprised of Anti-Microtubule Agents.
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.
authors.affiliation: Viventia Bio Inc., Winnipeg, MB R3T 3Z1, Canada. SChooniedass@viventia.com.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chooniedass
authors.affiliation: Viventia Bio Inc., Winnipeg, MB R3T 3Z1, Canada. RDillon@viventia.com.
authors.forename: Rachelle L
authors.initials: RL
authors.lastname: Dillon
authors.affiliation: Viventia Bio Inc., Winnipeg, MB R3T 3Z1, Canada. APremsukh@Viventia.com.
authors.forename: Arjune
authors.initials: A
authors.lastname: Premsukh
authors.affiliation: Avipep Pty Ltd., Parkville 3052, Victoria, Australia. Peter.Hudson@avipep.com.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hudson
authors.affiliation: Eleven Biotherapeutics, Philadelphia, PA 19104, USA. GAdams@viventia.com.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Adams
authors.affiliation: Eleven Biotherapeutics, Winnipeg, MB R3E 0W3, Canada. glen.macdonald@eleven.com.
authors.forename: Glen C
authors.initials: GC
authors.lastname: MacDonald
authors.affiliation: Viventia Bio Inc., Winnipeg, MB R3T 3Z1, Canada. JCizeau@viventia.com.
authors.forename: Jeannick
authors.initials: J
authors.lastname: Cizeau
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy; D002352:Carrier Proteins / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004926:Escherichia coli; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000737:chemistry; D008870:Microtubules / Q000187:drug effects*; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000068878:Trastuzumab
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C498282:ribosome-binding protein p34, human; D000068878:Trastuzumab
keywords: C6.5 diabody; HER2; deBouganin; immunotoxin; ribosome inactivating protein