DDIS-01. THE ANTIBODY-DRUG CONJUGATE ABT-414 DEMONSTRATES SINGLE-AGENT ANTI-CANCER ACTIVITY ACROSS A PANEL OF GBM PATIENT-DERIVED XENOGRAFTS

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2018-11, Vol.20 (suppl_6), p.vi69-vi69
• Main Authors: Marin, Bianca, Mladek, Ann, Burgenske, Danielle, He, Lihong, Hu, Zeng, Bakken, Katrina, Carlson, Brett, Schroeder, Mark, Sarkaria, Jann
• Format: Article
• Language: English
• Subjects: Abstracts
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noy148.280

Abstract ABT-414 is a novel antibody-drug conjugate (ADC) of monomethyl auristatin F (MMAF), a microtubule destabilizing agent, and an anti-EGFR antibody (ABT-806). ABT-414 has demonstrated promising efficacy in clinical trials against newly diagnosed and recurrent glioblastoma (GBM), but little is known about mechanisms of sensitivity and resistance to the drug. The efficacy of ABT-414 was evaluated in vitro across a panel of nine EGFR-amplified GBM patient-derived xenografts (PDXs). Six lines responded to therapy, with the EGFR vIII mutant lines (GBM6, GBM39, GBM76, GBM108) being more sensitive (IC50 ~0.01 ug/mL) than point mutant (GBM12) or wild-type (GBM84) amplified lines (IC50 ~0.5 ug/mL). In contrast, GBM26 (point mutant), GBM46 (vII mutant) and GBM59 (vIII mutant) were non-responsive (IC50 > 10 ug/mL). Further testing revealed that these latter three lines were also resistant to MMAE, a cell-permeable analog of MMAF, which suggests intrinsic resistance to the toxin. In the responsive lines, ABT-414 was further tested in tumors implanted in heterotopic and orthotopic locations using tumor volume measurements and/or bioluminescent imaging (BLI). In flank, GBM6, GBM39, GBM76 and GBM108 were all highly sensitive to therapy, with complete tumor regression observed in all mice extending beyond 200, 250, 130 and 50 days, respectively. Intracranial GBM39 tumors were also highly responsive, with continuous suppression of BLI signal to background, and a survival benefit greater than 155 days. In contrast, GBM6 was resistant to therapy, without detectable impact on tumor growth and a difference in median survival of 5 ± 10 days. GBM76 was intermediately sensitive, with an extension in median survival of 20 ± 10 days. In summary, the majority of EGFR amplified lines tested are sensitive to ABT-414 in vitro and as flank tumors, but efficacy in treatment of orthotopic tumors is more limited. We hypothesize this effect may be related to heterogeneity of drug delivery.