Tumor‐targeted antibody (mAb)/fragment‐conjugated nanoparticles (NPs) represent an innovative strategy for improving the local delivery of small molecules. However, the physicochemical properties of full mAb–NPs and fragment–NPs—that is, NP material, size, charge, as well as the targeting antibody moiety, and the linker conjugation strategies—remain to be optimized to achieve an efficient tumor targeting. A meta‐analysis of 161 peer‐reviewed studies is presented, which describes the use of tumor‐targeted mAb–NPs and fragment−NPs from 2009 to 2021. The use of these targeted NPs is confirmed to result in significantly greater tumor uptake of NPs than that of naked NPs (7.9 ± 1.9% ID g−1 versus 3.2 ± 0.6% ID g−1, respectively). The study further demonstrates that for lipidic NPs, fragment–NPs provide a significantly higher tumor uptake than full mAb–NPs. In parallel, for both polymeric and organic/inorganic NPs, full mAb–NPs yield a significant higher tumor uptake than fragment–NPs. In addition, for both lipidic and polymeric NPs, the tumor uptake is improved with the smallest sizes of the conjugates. Finally, the pharmacokinetics of the conjugates are demonstrated to be driven by the NPs and not by the antibody moieties, independently of using full mAb–NPs or fragment–NPs, confirming the importance of optimizing the NP design to improve the tumor uptake.
Background: management of head and neck squamous cell carcinomas (HNSCC) include anti-Epidermal Growth Factor Receptor (EGFR) antibodies and radiotherapy, but resistance emerges in most patients. RAS mutations lead to primary resistance to EGFR blockade in metastatic colorectal cancer but are infrequent in HNSCC, suggesting that other mechanisms are implicated. Since hypoxia and Hypoxia Inducible Factor-1 (HIF-1) have been associated with treatment failure and tumor progression, we hypothesized that EGFR/mammalian Target of Rapamycin (mTOR)/HIF-1 axis inhibition could radiosensitize HNSCC. Methods: We treated the radiosensitive Cal27 used as control, and radioresistant SQ20B and UD-SCC1 cells, in vivo and in vitro, with rapamycin and cetuximab before irradiation and evaluated tumor progression and clonogenic survival. Results: Rapamycin and cetuximab inhibited the mTOR/HIF-1α axis, and sensitized the SQ20B cell line to EGFR-inhibition. However, concomitant delivery of radiation to SQ20B xenografts increased tumor relapse frequency, despite effective HIF-1 inhibition. Treatment failure was associated with the induction of HIF-2α expression by cetuximab and radiotherapy. Strikingly, SQ20B and UD-SCC1 cells clonogenic survival dropped <30% after HIF-2α silencing, suggesting a HIF-2-dependent mechanism of oncogenic addiction. Conclusions: altogether, our data suggest that resistance to EGFR inhibition combined with radiotherapy in HNSCC may depend on tumor HIF-2 expression and underline the urgent need to develop novel HIF-2 targeted treatments.
Results: At primary analysis, 160 pts were randomised; all pts completed crossover tx; 44% completed continuation tx at cut-off (24-02-20). 136 pts (85%; 95% CI 79e90%) preferred SC; 22 (14%) preferred IV; 2 (1%) had no preference. Main reasons for SC preference: reduced clinic time (n¼119) and comfort during administration (n¼73). 141 (88%) were very satisfied or satisfied with SC vs. 108 (68%) with IV. 87% chose SC to complete HER2-targeted therapy. HCPs' perceptions on median pts' time in the tx room across cycles 1e6 for SC vs. IV admin were 33e50 vs. 130e300 min, respectively. The rates of serious adverse events (AEs) and grade 3 AEs were low; the most common AEs were as expected (table ).
579 Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2−positive breast cancer. HD201, developed by Prestige Biopharma Pte Ltd is a biosimilar candidate to Herceptin. The biosimilarity of HD201 was established based on systematic stepwise comparisons between HD201 and reference product, Herceptin. In order to confirm clinical similarity of HD201 to Trastuzumab, two clinical studies were undertaken. Methods: First, in a double-blind, randomised and parallel group study, 101 randomised healthy human subjects were subjected to a single 6 mg/kg IV dose by body weight over 90-min infusion of either HD201, EU- and US-Herceptin group by assessing pharmacokinetic (PK) and safety (TROIKA-I). The second study was a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) designed to compare the efficacy based on total pathological complete response rate (tpCR), safety, and pharmacokinetics of HD201 to EU-Herceptin in patients with HER2 positive early breast cancer. Each group of ~250 subjects were administered with either HD201 or EU-Herceptin in combination with chemotherapy in neoadjuvant followed by the antibody alone in the adjuvant phase. Results: TROIKA-I study demonstrated that HD201 was safe and well tolerated with comparable PK as EU- and US-Herceptin. Based on the neoadjuvant data from TROIKA study, the tpCR rate in the HD201 and Herceptin treatment groups was comparable and the 95% CI was included within the pre-defined margins of equivalence (Table). The incidence and severity of reported TEAEs did not imply any significant safety concerns and were comparable between both groups. In addition, the comparison of steady-state Ctrough between both arms in TROIKA study has established equivalence. Conclusions: The overall comparison exercise demonstrated the equivalence of HD201 to Herceptin. Clinical trial information: 2016-0040019-11 . [Table: see text]
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