nemorubicin (PNU 152243) / Nerviano Medical Sciences - LARVOL DELTA

Identification of antibody-drug conjugate payloads which are substrates of ATP-binding cassette drug efflux transporters. (PubMed, bioRxiv) - "All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the recently FDA-approved ADC mirvetuximab soravtansine, which has DM4 as the toxic payload, was decreased in cell lines with overexpression of P-gp. Several commonly used ADC payloads can be effluxed from cells by ABC transporters which may lead to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not substrates of ABC transporters."

Journal • Oncology • ABCB1 • ABCC1 • ABCG2

Development of antibody drug conjugates targeting MUC16 in ovarian cancer subtypes (AACR 2025) - "To exploit this target, we have systematically evaluated a panel of ADC payloads and linkers, including Auristatins (MMAE, MMAF), Camptothecin (SN-38), Maytansinoids, Calicheamicin, Nemorubicin, and Belotecan, conjugated to our proprietary antibody 4H11. The retained portion of MUC16 is a viable target for ADC development. The maytansinoid conjugates emerged as leading candidates for further preclinical evaluation and potential clinical development based on their broad spectrum of activity against multiple histological subtypes. Our findings further underscore preferential susceptibility of different OC histologic subtypes to different ADC payloads."

High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • MUC16

Recurrent pancreatic cancer treated with N-803 and PD-L1 t-haNK followed by an EGFR-targeted nanocell drug conjugate. (PubMed, Oncologist) - "The epidermal growth factor receptor-targeted antibody-nanocell conjugate E-EDV-D682 provides tumor-targeted chemotherapy in the form of its anthracycline metabolite PNU159682 (nemorubicin) cargo and is currently being studied in combination with immunomodulatory EDVs delivering the adjuvant α-galactosyl ceramide (GC)...Under the initial single-patient Investigational New Drug (spIND) protocol, the patient received N-803, PD-L1 t-haNK cells, and the albumin doxorubicin conjugate aldoxorubicin for ~27 months...Due to progression, a second spIND protocol was designed whereby the patient received E-EDV-D682 plus EDV-GC for more than 24 months, which resulted in stable disease and the patient's continued survival at the time this report was written. The patient's extended survival despite the dire prognosis associated with recurrent mPC points to the merits of this temporal combination regimen in overcoming immuno-chemo resistance with enhanced immune activity..."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • EGFR • IL15 • PD-L1

Preclinical assessment of GlycoConnect™ ADCs with potency-modulated derivatives of PNU-159,682 (AACR 2023) - "PNU-159,682 is an oxidized secondary metabolite of nemorubicin (MMDX), and substantially more potent (2100-6400-fold) than the commonly used chemotherapeutic anthracycline doxorubicin/adriamycin, but without the dose-limiting cardiotoxicity. Based on these beneficial features, PNU-159,682 is currently being clinically evaluated (phase 1) for solid tumor indications as a payload in various antibody-drug conjugates (NBE-002, SO-N102)...A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012."

Preclinical • Oncology • Solid Tumor

Antibody drug conjugates with anthracycline payload induce tumor-selective antitumor immunity and exhibit a favorable safety profile in cynomolgus monkey toxicology studies (AACR 2018) - "... Homogeneous ADCs targeting either HER2 or ROR1 have been generated by site-specific conjugation using sortase-enzyme mediated antibody conjugation (SMAC-TechnologyTM) with an ultra-potent, DNA damaging anthracycline toxin, based on the nemorubicin derivative PNU-159682... Homogeneous PNU-containing HER-2 and ROR1 ADCs show very high anti-tumor efficacy in vivo, both in PDX as well as in syngeneic solid tumor models - in case of HER-2 targeting, HER-2-PNU-ADCs exceeded efficacies of T-DM1 used as a benchmark ADC... Homogeneous PNU-containing HER-2 and ROR1 ADCs exhibit potent anti-tumor immunity in various in vivo tumor models and induce tumor-specific immunity in immune-competent syngeneic tumor models. In addition the ADCs display a very favorable therapeutic index and represent promising and safe drug candidates for treatment of various solid tumors."

Clinical • HER2 Breast Cancer

Evaluation of PNU-159682 antibody drug conjugates (ADCs). (PubMed, Bioorg Med Chem Lett) - "PNU-159682 is a highly potent secondary metabolite of nemorubicin belonging to the anthracycline class of natural products...Structure activity relationships were explored on the small molecule which led to six linker drugs being developed for conjugation to antibodies. Herein we describe the synthesis of novel PNU-159682 derivatives and the subsequent linker drugs as well as the corresponding biological evaluations of the small molecules and ADCs."

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