Abstract 5144: BT1718, a novel bicyclic peptide-maytansinoid conjugate targeting MT1-MMP for the treatment of solid tumors: Design of bicyclic peptide and linker selection
Autor: | Gavin Bennett, Diane Blakeley, Katerine Van Rietschoten, Robert J. Lutz, Helen Harrison, Silvia Pavan, Spencer Campbell, Liuhong Chen, Daniel Teufel, Peter U. Park, Amy E. Caruso Brown, Kevin A.W. Lee |
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Rok vydání: | 2017 |
Předmět: |
chemistry.chemical_classification
Cancer Research Protease Bicyclic molecule medicine.medical_treatment Peptide Hemopexin 02 engineering and technology 010501 environmental sciences 021001 nanoscience & nanotechnology Maytansinoid 01 natural sciences Molecular biology chemistry.chemical_compound Therapeutic index Oncology chemistry Biochemistry medicine 0210 nano-technology Linker 0105 earth and related environmental sciences Conjugate |
Zdroj: | Cancer Research. 77:5144-5144 |
ISSN: | 1538-7445 0008-5472 |
Popis: | Bicycles® are novel binding agents comprising small bicyclic peptides (1.5-3 KDa) constrained via a chemical scaffold, selected for high affinity and selectivity to targets of interest. MT1 (MMP14/MT1-MMP) is a membrane-associated metalloprotease overexpressed in many solid tumours and is implicated in tumor invasion and metastasis. MT1 expression positively correlates with poor prognosis. Phage libraries containing 1015 unique peptide sequences were post-translationally cyclized with thiol-reactive scaffold and used in an optimized, high-throughput selection process to identify Bicycles® to the hemopexin domain of MT1. Additional iterative rounds of directed phage based screening were used to optimize affinity and off-phage non-natural amino acids were introduced at select positions to improve plasma stability to generate the lead Bicycle binder. The lead anti-MT1 Bicycle was further modified with a sarcosyl spacer to form N241. N241 binds specifically to the hemopexin domain of MT1 with a Kd of approximately 2 nM with no binding observed to the catalytic domain of the protease nor to any of the related MMP family members tested. Importantly and in contrast to most antibodies, N241 binds with similar affinity to MT1 from multiple species including rodent, dog and non-human primate. Since the expected rapid tumor penetration and specific binding of these small peptidyl-binders makes them ideal for use in targeted delivery approaches, a series of Bicycle drug conjugates (BDCs) were prepared; N241 was conjugated to potent maytansinoid cytotoxics via linkers which varied in their cleavability. Though all the BDCs maintained high affinity for MT1, efficacy toward MT1-positive human tumor mouse xenografts varied with linker stability. BDCs with the most stable linkers were the least active suggesting that optimal tumor activation was obtained with linkers that could be cleaved more rapidly. Due to the rapid clearance and limited systemic exposure of these small-targeting BDCs, only the most labile linker showed toxicity in the mouse studies. Of the BDCs tested, BT1718, composed of N241 and DM1 conjugated via the SPP linker, demonstrated an optimal therapeutic index. Potent anti-tumor efficacy with BT1718 was observed across a panel of MT1-positive xenografts with complete tumor regressions observed in most models at doses that were well tolerated. In one example, HT-1080 fibrosarcoma subcutaneous xenografts were intraveneously treated with BT1718 when the tumor size had reached approximately 180 mm3. BT1718 given at 3 mg/kg once a week resulted in tumor stasis while BT1718 given at 10 mg/kg once a week or 3 mg/kg twice a week induced complete regression. In summary, BT1718, a highly active, targeted drug conjugate with unique pharmacological properties is a promising therapeutic candidate for the treatment of MT1-MMP-positive solid tumors. Citation Format: Helen Harrison, Gavin Bennett, Diane Blakeley, Amy Brown, Spencer Campbell, Liuhong Chen, Robert J. Lutz, Silvia Pavan, Katerine van Rietschoten, Daniel Teufel, Peter U. Park, Kevin Lee. BT1718, a novel bicyclic peptide-maytansinoid conjugate targeting MT1-MMP for the treatment of solid tumors: Design of bicyclic peptide and linker selection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5144. doi:10.1158/1538-7445.AM2017-5144 |
Databáze: | OpenAIRE |
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