Nano-pulse stimulation™ therapy (NPS™) is superior to cryoablation in clearing murine melanoma tumors.

Background: Nano-Pulse Stimulation™ Therapy (NPS™) is a new, bioelectric modality that applies ultrashort pulses of electric energy to trigger regulated cell death in treated tissues. Instead of initiating necrosis by heating or freezing, NPS therapy permeabilizes intracellular organelles to activate the cell's own self-destruct pathway of programmed or regulated cell death. Unlike cryotherapies that can both damage structural tissues and diffuse into the periphery beyond the margins of the lesion, NPS only affects cells within the treated zone leaving surrounding tissue and acellular components unaffected.

Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer.

Phosphatidylserine (PS) is a negatively charged phospholipid in all eukaryotic cells that is actively sequestered to the inner leaflet of the cell membrane. Exposure of PS on apoptotic cells is a normal physiological process that triggers their rapid removal by phagocytic engulfment under noninflammatory conditions via receptors primarily expressed on immune cells. PS is aberrantly exposed in the tumor microenvironment and contributes to the overall immunosuppressive signals that antagonize the development of local and systemic antitumor immune responses.

First-in-Man Evaluation of I-PGN650: A PET Tracer for Detecting Phosphatidylserine as a Biomarker of the Solid Tumor Microenvironment.

Purpose: PGN650 is a F(ab') antibody fragment that targets phosphatidylserine (PS), a marker normally absent that becomes exposed on tumor cells and tumor vasculature in response to oxidative stress and increases in response to therapy. PGN650 was labeled with I to create a positron emission tomography (PET) agent as an in vivo biomarker for tumor microenvironment and response to therapy. In this phase 0 study, we evaluated the pharmacokinetics, safety, radiation dosimetry, and tumor targeting of this tracer in a cohort of patients with cancer.

Phosphatidylserine Sensing by TAM Receptors Regulates AKT-Dependent Chemoresistance and PD-L1 Expression.

Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases that bind vitamin K-dependent endogenous ligands, Protein S (ProS), and growth arrest-specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNγR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity.

Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.

Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets.

Measuring response to therapy by near-infrared imaging of tumors using a phosphatidylserine-targeting antibody fragment.

Imaging tumors and their response to treatment could be a valuable biomarker toward early assessment of therapy in patients with cancer. Phosphatidylserine (PS) is confined to the inner leaflet of the plasma membrane in normal cells but is externalized on tumor vascular endothelial cells (ECs) and tumor cells, and PS exposure is further enhanced in response to radiation and chemotherapy. In the present study, we evaluated the potential of a PS-targeting human F(ab')2 antibody fragment, PGN650, to detect exposure of PS in tumor-bearing mice.

Targeting of humanized antibody D93 to sites of angiogenesis and tumor growth by binding to multiple epitopes on denatured collagens.

A humanized, affinity-matured IgG1 antibody, called D93, and its parental murine IgM HUI77 have been shown to specifically bind denatured collagens and thereby inhibit angiogenesis and tumor growth in various animal models. In this study, we have identified epitopes for both HUI77 and D93 on human collagen type IV. Several tryptic D93-binding peptides were identified by Western blot analysis and protein sequencing.

Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach.

Matrix metalloproteases (MMPs) secreted by both tumor and endothelial cells proteolytically degrade collagen during tumor growth and neo-vascularization. This exposes cryptic binding sites on collagen with functional relevance for angiogenesis. In this report, we characterized a novel humanized monoclonal IgG1 antibody, D93.

Rapid vascular regrowth in tumors after reversal of VEGF inhibition.

Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature.