Dataset Information

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.

ABSTRACT: Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen. The resulting ADC consisted of a human ?CD11a antibody (based on efalizumab clone hu1124) conjugated to an analog of the highly potent PDE4 inhibitor GSK256066. Both the human ?CD11a ADC and a mouse surrogate ?CD11a ADC (based on the M17 clone) rapidly internalized into immune cells and suppressed lipololysaccharide (LPS)-induced TNF? secretion in primary human monocytes and mouse peritoneal cells, respectively. In a carrageenan-induced air pouch inflammation mouse model, treatment with the ADC significantly reduced inflammatory cytokine production in the air pouch exudate. Overall, these results provide compelling evidence for the feasibility of delivering drugs with anti-inflammatory activity selectively to the immune compartment via CD11a and the development of tissue-targeted PDE4 inhibitors as a promising therapeutic modality for treating inflammatory diseases.

SUBMITTER: Yu S

PROVIDER: S-EPMC5167782 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.

Yu Shan S Pearson Aaron D AD Lim Reyna Kv RK Rodgers David T DT Li Sijia S Parker Holly B HB Weglarz Meredith M Hampton Eric N EN Bollong Michael J MJ Shen Jiayin J Zambaldo Claudio C Wang Danling D Woods Ashley K AK Wright Timothy M TM Schultz Peter G PG Kazane Stephanie A SA Young Travis S TS Tremblay Matthew S MS

Molecular therapy : the journal of the American Society of Gene Therapy 20161012 12

Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) th ...[more]

PMID: 27731313

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Project description:PurposeAnti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite clinical success of CDK4/6 inhibitors in hormone receptor-positive tumors, aggressive triple-negative breast cancers (TNBCs) are largely resistant due to CDK2/cyclin E expression, while free CDK2 inhibitors display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK inhibitor selected based on oncogene dysregulation, alongside patient subgroup stratification, may provide EGFR-targeted delivery.Experimental designExpression of G1/S-phase cell cycle regulators were evaluated alongside EGFR in breast cancer. We conjugated cetuximab with CDK inhibitor SNS-032, for specific delivery to EGFR-expressing cells. We assessed ADC internalization, and its anti-tumor functions in vitro and in orthotopically-grown basal-like/TNBC xenografts.ResultsTranscriptomic (6173 primary, 27 baseline and matched post-chemotherapy residual tumors), scRNA-seq (150290 cells, 27 treatment-naïve tumors) and spatial transcriptomic (43 tumor sections, 22 TNBCs) analyses confirmed expression of CDK2 and its cyclin partners in basal-like/TNBCs, associated with EGFR. Spatiotemporal live-cell imaging and super-resolution confocal microscopy demonstrated ADC colocalization with late lysosomal clusters. The ADC inhibited cell cycle progression, induced cytotoxicity against high EGFR-expressing tumor cells and bystander killing of neighboring EGFR-low tumor cells, but minimal effects on immune cells. Despite carrying a small fraction of the drug, the ADC restricted EGFR-expressing spheroid and cell line/patient-derived xenograft tumor growth.ConclusionsExploiting EGFR overexpression, and dysregulated cell cycle in aggressive and treatment-refractory tumors, a cetuximab-CDK inhibitor ADC may provide selective and efficacious delivery of cell cycle-targeted agents to basal-like/TNBCs, including chemotherapy-resistant residual disease.

Dataset Information

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.

Publications

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.

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