ensituximab (NEO-102) / Precision Biologics - LARVOL DELTA

In vitro and in vivo efficacy of the antibody-drug-conjugate (ADC) PB-vcMMAE-5 against human carcinoma expressing truncated core 2 O-glycans (SITC 2025) - "PB-223 was created through affinity maturation of NEO-102, a chimeric human IgG1 mAb that targets tumor specific truncated core-2 O-glycans. A dose escalation study of 1,3,6, and 9 mg/kg is ongoing. These findings support its potential as broad-spectrum therapeutic agent against tumors expressing truncated core 2 O-glycans."

Preclinical • Lung Cancer • Lung Non-Small Cell Squamous Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR

QUILT-3.010: A Study of Gemcitabine and Nab-paclitaxel With or Without NPC-1C to Treat Patients With Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=81 | Terminated | Sponsor: Precision Biologics, Inc | Phase classification: P2 ➔ P1/2

Phase classification • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Development and characterization of an antibody-drug conjugate (ADC) utilizing PB-223, a novel monoclonal antibody (mAb) specifically targeting core 2 O-glycans on human carcinomas (AACR 2025) - "The mAb PB-223 was developed through the affinity maturation of mAb NEO-102, a chimeric human IgG1 mAb that specifically targets truncated Core-2 O-glycans, found in colorectal and pancreatic cancers...At a concentration of 10nM, DS-8201 inhibited cell proliferation by 82.39%... In this study, we developed PB-223 ADCs and evaluated their anti-tumor efficacy using an in vitro model. We assessed three PB-223 ADCs: PB-MMAE-2, PB-MMAE-5 and PB-MMAE-6. Our findings highlight the potential of these ADCs as innovative options for treating human carcinomas expressing core 2 O-glycans."

Breast Cancer • Colorectal Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor

Affinity maturation and characterization of a novel O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) PB-223 (SITC 2024) - "NEO-102 (Ensituximab) is a chimeric human IgG1 mAb targets a glycosylated variant of MUC5AC with specificity to colorectal and pancreatic cancer...In addition, PB-223 can be internalized in the PB-223 antigen positive cell line OV-90. This finding supports PB-223 as a potential candidate for the development of antibody-drug conjugates for treatment of various human carcinomas."

Colorectal Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • MUC5AC

Affinity maturation and characterization of a novel O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) PB-223 (SITC 2024) - "NEO-102 (Ensituximab) is a chimeric human IgG1 mAb targets a glycosylated variant of MUC5AC with specificity to colorectal and pancreatic cancer...In addition, PB-223 can be internalized in the PB-223 antigen positive cell line OV-90. This finding supports PB-223 as a potential candidate for the development of antibody-drug conjugates for treatment of various human carcinomas."

Colorectal Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • MUC5AC

Precision Biologics to Announce Development of New Monoclonal Antibody (mAb) PB-223 at SITC, Houston, TX, November 7-8, 2024 (PRNewswire) - "The objective of this study was to enhance the binding affinity of NEO-102 to its target antigen...This new biologic asset developed by affinity maturation was given the name PB-223...Results show that PB-223 has a KD of 4.5-fold less than NEO-102, suggesting a higher affinity for the target antigen by PB-223 compared to NEO-102...Flow cytometry analysis showed that PB-223 not only has markedly enhanced comparative binding to colorectal and pancreatic cancer cell lines recognized by NEO-102, but that PB-223 is also able to bind to many additional tumor cell lines that were not recognized by NEO-102. Further study by O-glycan array analysis showed that 1) PB-223 binds specifically to core-2 O-glycans, and that 2) core 2 O-glycans recognized by PB-223 are expressed on tumor cell lines positive for PB-223 binding in flow cytometry."

Preclinical • Bladder Cancer • Colorectal Cancer • Head and Neck Cancer • Kidney Cancer • Liver Cancer • Pancreatic Cancer • Prostate Cancer • Triple Negative Breast Cancer

Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial. (PubMed, JAMA Netw Open) - P2 | "Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. ClinicalTrials.gov Identifier: NCT01834235."

Clinical • Journal • Metastases • Hematological Disorders • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CA 19-9 • MUC5AC

Purification and structure of luminal domain C of human Niemann-Pick C1 protein. (PubMed, Acta Crystallogr F Struct Biol Commun) - "The crystals belonged to space group P2 and diffracted to 2.3 Å resolution. The structure is similar to other reported structures of NPC1-C, with differences observed in the protruding loops when compared with NPC1-C in complex with Ebola virus glycoprotein or NPC2."

Journal • Infectious Disease • NPC2

Understanding the Clinical Impact of MUC5AC Expression on Pancreatic Ductal Adenocarcinoma. (PubMed, Cancers (Basel)) - "NPC-1C and PAM4 antibody reactive epitopes on MUC5AC are immunogenic and could represent specific changes on the native MUC5AC glycoprotein linked to carcinogenesis. It was never studied to predict treatment response."

Clinical • Journal • Review • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • MUC5AC

ORP2 couples LDL-cholesterol transport to FAK activation by endosomal cholesterol/PI(4,5)P exchange. (PubMed, EMBO J) - "Moreover, ORP2 increases PI(4,5)P in NPC1-containing late endosomes in a FAK-dependent manner, controlling their tubulovesicular trafficking. Together, these results provide evidence that ORP2 controls FAK activation and LDL-cholesterol plasma membrane delivery by promoting bidirectional cholesterol/PI(4,5)P exchange between late and recycling endosomes."

Journal • Dyslipidemia

Structural Insights into the Interaction of Filovirus Glycoproteins with the Endosomal Receptor Niemann-Pick C1: A Computational Study. (PubMed, Viruses) - "In the present study, we performed molecular modeling and molecular dynamics simulations of NPC1 complexed with GPcls of two ebolaviruses, EBOV and Sudan virus (SUDV), and one marburgvirus, Ravn virus (RAVV)...These structural differences may affect the size and/or shape of the receptor-binding pocket of GPcl. Our structural models could provide useful information for improving our understanding the differences in host preference among filoviruses as well as contributing to structure-based drug design."

Journal • Infectious Disease

NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes. (PubMed, EMBO J) - "NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease."

Journal • CNS Disorders

Image-based screen capturing misfolding status of Niemann-Pick type C1 identifies potential candidates for chaperone drugs. (PubMed, PLoS One) - "We previously identified a series of oxysterol derivatives and phenanthridine-6-one derivatives as pharmacological chaperones, i.e., small molecules that can rescue folding-defective phenotypes of mutated NPC1, opening up an avenue to develop chaperone therapy for Niemann-Pick disease type C. Here, we present an improved image-based screen for NPC1 chaperones and we describe its application for drug-repurposing screening. We identified some azole antifungals, including itraconazole and posaconazole, and a kinase inhibitor, lapatinib, as probable pharmacological chaperones...Competitive photo-crosslinking experiments suggested that oxysterol-based chaperones and itraconazole share the same or adjacent binding site(s), and the sensitivity of the crosslinking to P691S mutation in the sterol-sensing domain supports the hypothesis that their binding sites are located near this domain. Although the azoles were less effective in reducing cholesterol accumulation than the..."

Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Metabolic Disorders

Application of a glycinated bile acid biomarker for diagnosis and assessment of response to treatment in Niemann-pick disease type C1. (PubMed, Mol Genet Metab) - "The test showed sensitivity of 0.9945 and specificity of 0.9982 to differentiate individuals with NPC1 from NPC1 carriers and controls...Plasma TCG was significantly reduced after intravenous (IV) 2-hydroxypropyl-β-cyclodextrin (HPβCD) treatment. These results demonstrate that plasma TCG was superior to C-triol and PPCS as NPC1 diagnostic biomarker and was able to evaluate the peripheral treatment efficacy of IV HPβCD treatment."

Biomarker • Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Metabolic Disorders

A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export. (PubMed, Nat Commun) - "We find that active Rab7 interacts with the NPC1 cholesterol transporter and licenses lysosomal cholesterol export. This process is abolished in C18orf8-, Ccz1- and Mon1A/B-deficient cells and restored by a constitutively active Rab7. The trimeric Mon1-Ccz1-C18orf8 (MCC) GEF therefore plays a central role in cellular cholesterol homeostasis coordinating Rab7 activation, endosomal LDL trafficking and NPC1-dependent lysosomal cholesterol export."

Journal • C18orf8

Cholesterol binding to the sterol-sensing region of Niemann Pick C1 protein confines dynamics of its N-terminal domain. (PubMed, PLoS Comput Biol) - "NPC1 contains a transmembrane sterol-sensing domain (SSD), which is supposed to regulate protein activity upon cholesterol binding, but the mechanisms underlying this process are poorly understood...The additional presence of an NTD-bound cholesterol suppresses the flexing of the NTD. We propose that cholesterol acts as an allosteric effector, and the modulation of NTD dynamics by the SSD-bound cholesterol constitutes an allosteric feedback mechanism in NPC1 that controls cholesterol abundance in the lysosomal membrane."

Journal • NPC2

[VIRTUAL] Clinical Development of Monoclonal Antibodies Targeting Tumor Neoepitopes (IOS 2020) - "In addition, a second novel monoclonal antibody, NEO-201 with a different tumor target and various mechanisms of action is currently in clinical trials. Combination approaches are currently being studied based on these mechanisms with Ph2 studies planned in a variety of tumors that express its target."

Clinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

"Ensituximab Shows Modest Single-Agent Activity in CRC, Combinations to Be Explored @MoffittNews #crcsm https://t.co/xpm0txQJJg" (@OncLive)

Colorectal Cancer • Gastrointestinal Cancer • Oncology

Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer. (PubMed, Clin Cancer Res) - "Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory CRC."

Clinical • Journal • P2 data • Colorectal Cancer • Constipation • Fatigue • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Oncology • Solid Tumor

QUILT-3.010: A Study of Gemcitabine and Nab-paclitaxel With or Without NPC-1C to Treat Patients With Pancreatic Cancer (clinicaltrials.gov) - P2; N=81; Terminated; Sponsor: Precision Biologics, Inc; Trial completion date: Sep 2018 ➔ Dec 2019; Active, not recruiting ➔ Terminated; DSMB terminated the trial for futility.

Clinical • Trial completion date • Trial termination

Characterization of PnpC1C2, a “type II” hydroquinone ring-cleaving dioxygenase (ACS-Sp 2019) - "NMR studies were performed to determine the regiospecificity of ring cleavage with monosubstituted hydroquinones. These results showed notable differences for both the substrate specificity and ring-cleavage regiospecificity of PnpC1C2 compared to that of PcpA, a member of the Type I hydroquinone dioxygenase family, which is structurally related to well-studied catechol extradiol dioxygenase enzymes."