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.
Highlights
Antibody Drug Conjugates (ADCs) are comprised of a full-length antibody chemically conjugated to small molecule payloads via a linker [1]
The titration curve of deB-C6.5-diab reactivity to HER2-positive cells was similar to that of equimolar concentrations of the control C6.5 diabody suggesting that the addition of deBouganin did not alter the diabody binding affinity (Figure 1B)
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Summary
Antibody Drug Conjugates (ADCs) are comprised of a full-length antibody chemically conjugated to small molecule payloads via a linker [1]. With the approval of brentuximab vedotin (SGN-35) and ado-trastuzumab-emtansine (T-DM1), along with more than 50 different ADCs currently in clinical trial, this class of anti-cancer agents represents a targeted drug alternative to the non-specific action of chemotherapeutic agents and radiation treatments [2,3,4]. The benefit of targeting highly potent payloads directly to the tumor cells using antibodies has resulted in a lower toxicity profile and meaningful clinical responses [5]. DNA binding agents such as calicheamicin, pyrrolobenzodiazepine dimer (PBD), or duocarmycin represent the majority of payloads currently in use for ADCs [6]. The average drug antibody ratio (DAR) varies between 2 and 4 and depends on the nature of the payload and the type of conjugation
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