Somatostatin receptor 2 targeting peptide modifications for peptide-drug conjugate treatment of small cell lung cancer
Abstract
Peptide-drug conjugate (PDC) represents a special therapeutic strategy to enhance drug delivery by targeting tumor cell receptors while minimizing off-target effects. Comparing the antibody-drug conjugate (ADC), the targeting peptide constitutes the pivotal component of PDC, especially with easy optimization of peptides to promote their in vivo stability, and with the agonist stimulated GPCR internalization to facilitate drug distribution into tumor cell plasma. Herein, we have optimized a highly stable peptide molecule LanTC targeting somatostatin receptor 2 (SSTR2), through amino acid substitution and disulfide bond modification from an FDA proved peptide drug Lanreotide. The LanTC based PDC was constructed through conjugation of the cytotoxic drug emtansine (DM1). The LanTC-DM1 PDC exhibited high stability and high agonist affinity to SSTR2. Subsequent in vitro and in vivo pharmacological data revealed that LanTC-DM1 PDC exhibited antitumor activity in small cell lung cancers (SCLC) which was known to have over-expressing SSTR2. The LanTC-DM1 PDC with specific targeting and antitumor activity provides a solid basis not only for advancing SSTR2-targeted PDCs as a promising therapy for SCLC, but also for other PDC developments targeting GPCRs in plasma membrane of tumor cells.
Keywords:
peptide modification; Somatostatin Receptor 2; Peptide-Drug Conjugate (PDC); small cell lung cancer; anti-tumor efficacy; Cryo-EM