Trastuzumab-deBouganin Conjugate Overcomes Multiple Mechanisms of T-DM1 Drug Resistance

Abstract

The development of antibody drug conjugates has provided enhanced potency to tumor-targeting antibodies by the addition of highly potent payloads. In the case of trastuzumab-DM1 (T-DM1), approved for the treatment of metastatic breast cancer, the addition of mertansine (DM1) to trastuzumab substantially increased progression-free survival. Despite these improvements, most patients eventually relapse due to complex mechanisms of resistance often associated with small molecule chemotherapeutics. Therefore, identifying payloads with different mechanisms of action (MOA) is critical for increasing the efficacy of targeted therapeutics and ultimately improving patient outcomes. To evaluate payloads with different MOA, deBouganin, a deimmunized plant toxin that inhibits protein synthesis, was conjugated to trastuzumab and compared with T-DM1 both in vitro and in vivo. The trastuzumab-deBouganin conjugate (T-deB) demonstrated greater potency in vitro against most cells lines with high levels of Her2 expression. In addition, T-deB, unlike T-DM1, was unaffected by inhibitors of multidrug resistance, Bcl-2-mediated resistance, or Her2-Her3 dimerization. Contrary to T-DM1 that showed only minimal cytotoxicity, T-deB was highly potent in vitro against tumor cells with cancer stem cell properties. Overall, the results demonstrate the potency and efficacy of deBouganin and emphasize the importance of using payloads with different MOAs. The data suggest that deBouganin could be a highly effective against tumor cell phenotypes not being addressed by current antibody drug conjugate formats and thereby provide prolonged clinical benefit.

Targeted dianthin is a powerful toxin to treat pancreatic carcinoma when applied in combination with the glycosylated triterpeneSO1861

“…This strategy was already successful in the past (Gilabert-Oriol et al, 2013c;von Mallinckrodt et al, 2014); however, it required careful choice of the length of the time period between SO1861 and toxin application (Bachran et al, 2010a). With respect to clinical trials, the use of a deimmunized form of dianthin might facilitate systemic applications as shown for a deimmunized form of another ribosome-inactivating protein, bouganin, in an immunotoxin with trastuzumab (Dillon et al, 2016). Another possibility is to substantially decrease the systemic concentration of SO1861 by modifying the enhancer to a targeted molecule.…”

Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

“…Also, it has been suggested a combination of inhibitors of the chaperone HSP90 that promote HER2 targeting to lysosomes and its degradation suggested as a new strategy to improve therapy with T-DM1 (35). In addition to this, other novel anti-HER2 antibody-drug conjugate offer promising activity in T-DM1-pretreated breast cancer (36,37). Other potential mechanisms of resistance that come from the trastuzumab part of the T-DM1 molecule have not proven its clinical utility when assayed in patient samples from clinical trials (9,11).…”

Tumor stroma–targeted antibody-drug conjugate triggers localized anticancer drug release

“…However, because other tumors may acquire or intrinsically express P-gp, assessing P-gp expression in tumor cells could represent a useful diagnostic biomarker to guide patient selection and ensure that the TEM8-ADC is given to those most likely to respond. Moreover, because MMAE, DM-1, and calicheamicin are all substrates of P-gp (45,46), these results have potential implications for clinically approved ADCs and many others in clinical development. Identifying alternative payloads that are insensitive to drug-efflux pumps like P-gp could be particularly valuable for patients whose tumor cells are P-gp + .…”