Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
The development of antibody drug conjugates (ADC) holds significant promise for improving outcomes in patients with cancer. However, toxicity can limit the number of accessible targets for these highly potent and empowered antibody formats due to expression in healthy tissue. Probody formatted ADCs enable opening up the therapeutic window for high potential but previously inaccessible targets, such as the Jagged ligands in the Notch pathway. Probodies are fully recombinant biotherapeutics comprised of a monoclonal antibody whose binding to target antigen is blocked by a masking peptide. Upon cleavage of a specific substrate-linker by tumor-specific proteases, the activated Probody binds its target, resulting in tumor-localized activity. Jagged expression is observed in a wide variety of patient tumors including multiple myeloma, pancreatic cancer, breast cancer, and prostate cancer. We previously described a novel anti-Jagged 1/2 antibody that is efficacious in slowing tumor growth in mouse in-vivo tumor models but results in systemic toxicity. A corresponding Probody mitigates systemic toxicities associated with inhibition of Jagged-induced Notch signaling while maintaining anti-tumor efficacy.
Here we show that the Notch ligands Jagged 1 and Jagged 2 have properties that could also enable an antibody-drug conjugate (ADC) approach because the ligands are both expressed on the cell surface and can internalize an anti-Jagged antibody. Using FACS we have shown that Jagged 1/2 are expressed on several human cancer cell lines and by fluorescent IHC staining, the expression of Jagged 1/2 is maintained in the corresponding xenograft tumors. To further explore the potential of Jagged as an ADC target, we engineered a Probody Drug Conjugate (PDC) conjugated to the microtubule inhibitor MMAE. This PDC is efficacious in a pancreatic xenograft tumor model BxPC3. Importantly, in the BxPC3 model the PDC shows equivalent in vivo efficacy to the corresponding ADC without causing the systemic toxicity associated with ADC treatment. Supportive of the potential clinical benefit of an anti-Jagged PDC, more than 75% of lung, pancreatic, and breast cancer patient tumor samples evaluated show moderate to high Jagged 1/2 expression as measured by IHC staining. These data demonstrate that the ProbodyTM platform has potential to enable the use of drug conjugates to target Jagged ligands in the Notch pathway.
Citation Format: Jason Sagert, Jim West, Chihunt Wong, Luc Desnoyers, Olga Vasiljeva, Jennifer Richardson, Krishna Polu, Henry Lowman. Transforming Notch ligands into tumor-antigen targets: A Probody-Drug Conjugate (PDC) targeting Jagged 1 and Jagged 2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2665. doi:10.1158/1538-7445.AM2014-2665