Targeting CD30L in B-cell non-Hodgkin lymphoma: novel peptide conjugates and their therapeutic potential.

BACKGROUND: B-cell non-Hodgkin lymphoma (B-NHL) constitutes the majority of NHL cases. Patients with B-NHL often experience multiple recurrences, necessitating several lines of antitumor therapy, and develop drug resistance. The recent success of therapeutic strategies targeting CD19 and CD20 highlights the therapeutic potential of identifying unique molecular markers in B-NHL for precision medicine, although challenges like immunogenicity and limited tumor penetration persist. METHODS: In this study, whole-cell phage display was employed to identify the specific binding peptide TG-1 towards B-NHL cells which was confirmed in vitro and in vivo, and its corresponding target CD30 ligand (CD30L) was identified by mass spectrometry and validated by functional assays, molecular docking, bioinformational analyses, knockdown, and rescue experiments. Additionally, the effects of TG-1 and functional roles of CD30L in B-NHL cells were investigated by exploring the molecular mechanisms of CD30/CD30L interactions. Furthermore, TG-1 peptide and doxorubicin co-functionalized gold nanoparticles (AuNPs) were characterized, and their effects on B-NHL cell proliferation were studied both in vitro and in vivo. RESULTS: Here, we identified and validated the CD30L as a novel target on B-NHL cells, along with its highly specific binding peptide TG-1, using whole-cell phage display. TG-1 binds CD30L, impairing lymphoma cell viability by disrupting the CD30-CD30L signaling axis, which is crucial for B-NHL cell survival. It demonstrates strong inhibitory effects on lymphoma cell proliferation both in vitro and in vivo. Additionally, the peptide and doxorubicin co-functionalized AuNPs demonstrated significant inhibitory effects on B-NHL cell proliferation, highlighting their potential as a promising therapeutic strategy. CONCLUSIONS: In summary, our findings underscore the potential of CD30L as a novel target for B-NHL treatment and demonstrate the promise of CD30L-targeted peptides in advancing precision medicine for B-NHL, paving the way for future clinical developments.