English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap) 2 -E1-(Rap) 2  and (Rap) 2 -E1*-(Rap) 2 , comprising four copies of Rap linked to the C H 3 and C K  termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC).    Methods  The DNL-based immunoRNases, (Rap) 2 -E1-(Rap) 2  and (Rap) 2 -E1*-(Rap) 2 , were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model.    Results  (Rap) 2 -E1-(Rap) 2  was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC 50  ≤ 1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap) 2 -E1-(Rap) 2 , generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap) 2 -E1-(Rap) 2  in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap) 2 -E1-(Rap) 2  was less effective (EC 50  > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap) 2 -E1*-(Rap) 2  when given the maximal tolerated dose.    Conclusions  A new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap) 2 -E1-(Rap) 2  and (Rap) 2 -E1*-(Rap) 2  support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer