Antibody News

Autophagy Inhibition in Cancer: Clinical Trials Update

Tuesday, June 19, 2018 - 10:43
Autophagy signaling pathway

By Christina Towers, PhD.

Autophagy mediates the recycling of damaged cellular material into building blocks like amino acids and other necessary nutrients that can fuel metabolism and cell growth, especially under nutrient depleted conditions. There are currently over 60 clinical trials reported on ClinicalTrials.gov that are either completed or on-going using autophagy inhibition, mostly in combination with other targeted therapies. Autophagy has a pro-tumorigenic role in established tumors and consequently the vast majority of clinical trials focus on autophagy inhibition in cancer. Over the last decade, a dozen Phase I and I/II clinical trials...

Adenosine Inhibits T cell Tumor Infiltration: KCa3.1, a New Anticancer Target

Tuesday, June 12, 2018 - 11:47
CD8 alpha antibody, ICC

By Yoskaly Lazo-Fernandez, PhD

Role of Adenosine in the Tumor Microenvironment a Target for Cancer Therapy

The tumor microenvironment (TME) tends to be concentrated in the purine nucleoside adenosine, a direct result of the hypoxia normally associated with cancer. Extracellular adenosine binds to its receptor, A2A receptor (A2AR), in the surface of lymphocytes and other immune cells resulting in anti-inflammatory and immunosuppressive responses1 which correlate with higher tumor progression and poor prognosis in cancer patients2. Extracellular adenosine accumulation...

Crosstalk Between Oxidative Stress and Autophagy

Tuesday, June 5, 2018 - 11:10
Autophagosome and lysosome fusion

By Christina Towers, PhD.

Role of Reactive Species in Cellular Function

Oxidative stress is a byproduct of an imbalance between oxidants and antioxidants present in the cell resulting in dysfunctional redox signaling. This disproportion is caused by naturally occurring reactive oxygen species (ROS) and reactive nitrogen species (RNS) that can be derived from either extracellular sources or intracellularly as byproducts of essential cellular processes like metabolism. These species oxidize and remove electrons from the molecules they interact with including many kinds of biomolecules which can be detrimental to overall cellular function1. For example, ROS can induce...

Novel Approaches to Improve Efficacy and Safety of CAR-T Therapy

Tuesday, May 29, 2018 - 08:44
CAR-T Therapy

By Jacqueline Carrico, BS, MD Candidate

Given the rapid advances in CAR-T therapy, there have been major efforts to improve the specificity and safety of these therapies. Very few targets exist that are only expressed in the malignant cell population, resulting in on-target/off-tumor toxicities. Most have been minor and controllable; however, several trials have been terminated due to severe and life-threatening toxicities. There is increasing concern about this problem with dually targeted therapies, such as dual-CAR or tandem CAR.

Synthetic Notch Receptors

One approach to increasing on-tumor specificity is the development of CAR-T cells that express synthetic...

Lysosomal Dysfunction is Linked to Exosomal Secretion

Tuesday, May 22, 2018 - 09:50
CAR-T Poster

By Christina Towers, PhD.

Lysosomal Dysfunction and Disease

Lysosomes are highly acidic organelles that are critical for cellular function and indispensable for degradative pathways like autophagy and endocytosis.  There are a number of different diseases that have been associated with lysosomal dysfunction, the most detrimental being neurological disorders including Huntington's Disease, Alzheimer's disease, and Parkinson's disease.  Other rare neurological diseases like Niemen-Pick disease Type C (NPC) have been directly linked to familial-mutations in endolysosomal genes.  All of these disorders are attributed to a buildup of the detrimental...

Targeting Success in CAR-T Therapy for Solid Tumors

Tuesday, May 15, 2018 - 09:40
CAR-T poster

By Jacqueline Carrico, BS, MD Candidate

Targeting Success in CAR-T Therapy for Solid Tumors

Developing successful CAR-T therapy requires identification of specific tumor-associated antigens, as the primary target for CAR-T binding and activation. Some solid tumors have well-characterized oncogenes which play a pivotal role in tumor cell proliferation, migration, and survival. These oncogenes are ideal targets for CAR-T therapy, particularly when the oncogene is expressed at low levels in normal tissues.

Epidermal Growth Factor Receptor (EGFR)

The tyrosine kinase receptor EGFR, is aberrantly expressed in non-small cell lung cancer (NSCLC),...

Mitochondrial ATPase inhibitory factor 1 (IF1) provides an explanation of cancer growth in anoxia or pseudo-anoxia

Tuesday, May 8, 2018 - 09:29
ATPase inhibitor factor 1 antibody ICC

By Jamshed Arslan Pharm.D.

Adenosine triphosphate (ATP) is the major life’s energy-carrying molecule. It is mainly produced by mitochondrial ATP synthase (Complex V) through oxidative phosphorylation (Oxphos). For example, Oxphos-dependent oxidation of a glucose molecule generates about 30 molecules of ATP. In Oxphos, respiratory chain (r.c.) complexes catalyze the transfer of electrons from energy-rich molecules (NADH or FADH2) to oxygen (O2) and...

TGF-beta for treating degenerative intervertebral disc disease

Tuesday, May 1, 2018 - 09:32
TGF-beta poster

By Jamshed Arslan Pharm.D.

Our upright posture and balance depend on a jelly-like material, called nucleus pulposus (NP), in the middle of intervertebral discs. NP cells protect us from disc degeneration by maintaining optimal amounts of proteoglycans (proteins bonded to glycosaminoglycans) in the NP matrix. This process can be facilitated by TGF-beta, which stimulates the synthesis of sulfated glycosaminoglycan (sGAG) and chondroitin sulfate proteoglycan 1 in the NP cells. The synthesis of sGAG depends on chondroitin polymerizing factor (ChPF), an enzyme that extends the chondroitin sulfate (CS) backbone in sGAG. However, the...

Autophagy independent roles of the core ATG proteins

Tuesday, April 24, 2018 - 11:24
ATG5 ICC Antibody

By Christina Towers, PhD.

Autophagy and ATG Proteins

Autophagy is a nutrient recycling process that cells use to fuel metabolism, particularly in response to nutrient deprivation.  It is critical for removal of damaged proteins as well as clearing certain infections.  It is a complex process that involves over 20 core autophagy genes (ATGs), most of which were originally identified in yeast but the mammalian homologs have now been well characterized.

The formation of a double membrane vesicle termed the phagophore is initiated by the ULK complex where the protein kinases ULK1 and...

Immunity’s flipside: Microglia promote Alzheimer’s pathology during inflammation

Tuesday, April 17, 2018 - 11:04
ICC Amyloid beta antibody

By Jamshed Arslan Pharm.D.

Microglia are brain's macrophages. In Alzheimer's disease (AD), microglia clear up protein aggregates called amyloid beta plaques. The connection between immune activation and AD is unclear, but a major sensor for danger-signals, called NLRP3 inflammasome, is known to be activated in the brains of patients and transgenic mice (APP/PS1) that overproduce amyloid beta.1 Activated NLRP3 inflammasome leads to the release of pro-inflammatory cytokine (IL-1 beta...

Nuclear LC3: Why is it there and what is it doing?

Tuesday, April 10, 2018 - 09:17
hHpr1-p84-Thoc1 Antibody

By Christina Towers, PhD.

Cells use the complex process of autophagy to degrade and recycle cytoplasmic material.  There are over 20 proteins that have been implicated in this process and appropriately named core autophagy genes (ATGs).  Most of these were originally discovered in yeast, arguably the most famous being ATG8.  In higher eukaryotes ATG8 evolved into a family of proteins known as the GABA type A receptor-associated protein (GABARAP), which includes the Microtubule Associated Protein 1 light chain 3 (MAP1LC3), better known...

CAR-T Cell Therapy: Refining the Approach in Solid Tumors

Tuesday, April 3, 2018 - 08:30
CAR-T Cell Killing

By Jacqueline Carrico, BS, MD Candidate

Chimeric antigen receptor T-cells, better known as CAR-T cells, are being used as a novel anticancer therapy. CAR-T cells are engineered T-cells which express a modified antigen-receptor. Each chimeric antigen receptor contains 3 domains: an extracellular binding domain, a transmembrane hinge domain, and an intracellular activation or costimulatory domain. The extracellular portion is the single chain variable fragment (scFv), made up of an antibody-derived heavy chain and light chain, which ultimately recognize specific tumor antigens. The intracellular activation domain allows T-cell activation upon...

Killing two birds with one stone: Treating inflammation and cancer by inhibiting prolyl-4-hydroxylase-1

Tuesday, March 27, 2018 - 10:41
Bi-directional Cross-talk Between HIF1-alpha and NF kappa B

By Jamshed Arslan Pharm.D.

The cell’s oxygen-sensing machinery comprises prolyl-4-hydroxylases (P4Hs 1-3, PHDs 1-3, or EGLN 1-3) and their canonical target hypoxia-inducible factors (HIFs). When oxygen levels are low, PHDs become functionally inactive, leading to HIFs’ stability. PHD1 is thought to provide a link between hypoxia and inflammation, partly because it influences the prototypical proinflammatory transcription factor NF-kB in such a way that suppressing PHD1 reduces inflammation....

Getting Physical: Link between Lipid Metabolism and Hypoxia Target Genes

Tuesday, March 20, 2018 - 11:16
Autophagy Mechanisms

By Jamshed Arslan Pharm.D.

von Hippel-Lindau (VHL) disease is associated with tumors arising in multiple organs. Activation of hypoxia-inducible factor (HIF)-alpha underlies the VHL disease pathogenesis. In normoxia, VHL tumor-suppressor protein (pVHL) and E3 ubiquitin ligase lead to proteosomal degradation of HIF-alpha. In hypoxia, HIF-alpha escapes degradation, partly because pVHL binding to HIF-alpha depends on a posttranslational modification (hydroxylation of proline residues) on HIF-alpha that only occurs in normoxia. The exact role of pVHL in tumor hypoxia, when HIF-alpha is stabilized, is poorly...

Autophagy inhibition in pediatrics: One physician-scientist’s brave decision

Tuesday, March 13, 2018 - 13:05
Autophagy Pathway

By Christina Towers, PhD.

The current time from when a discovery is first made on the bench to when that discovery might translate into an approved therapy in cancer patients is an astounding 10-15 years. Scientists and clinicians alike face a daunting uphill battle to find novel targeted therapies that can improve a patient’s outcome yet still maintain minimal adverse side effects.  However, recently Dr. Jean Mulcahy Levy, a pediatric neuro-oncologist and physician-scientist, found a way to bypass some of these hurdles.  In 2012 she was working as a research-fellow at the University of Colorado in the laboratory of Dr. Andrew Thorburn, an expert in the field of...

Cleaner gone bad: Autophagy regulates motor neuron loss in spinal muscular atrophy

Wednesday, March 7, 2018 - 11:10
Autophagy Mechanisms

By Jamshed Arslan Pharm.D.

Neuromuscular disorders affect the peripheral nervous system and muscles. Spinal muscular atrophy (SMA) is one such incurable disease in which muscles fail to receive signals from the spinal motor neurons (MNs), and consequently, weaken due to inactivity. MN degeneration and muscle atrophy lead to the premature death of the victims. Like most of the neuromuscular disorders, SMA is genetic, and its genetic causes are known: the inactivation of survival motor neuron 1 (SMN1) gene, which reduces the...

Autophagy in the Tumor Microenvironment

Tuesday, February 27, 2018 - 13:32
Biogenesis Molecular

By Christina Towers, PhD.

The last 20 years of cancer research have taught us the vast complexities of this life-altering disease. In the last 5 years we have realized that those complexities might extend beyond the cancer cells.  The role of the tumor microenvironment (TME) is now front and center in almost every aspect of cancer biology, and autophagy is no exception.  The TME consists of a gamut of different cell types that include supporting stroma like fibroblasts and endothelial cells, as well as immune cells. Recent reports have indicated an important role for autophagy in the crosstalk between...

Cross-talk between proteasome degradation and lysosomal degradation

Tuesday, February 20, 2018 - 11:39
Autophagy Pathway

By Christina Towers, PhD.

Misfolded and damaged proteins are degraded by two canonical mechanisms in the cell including the ubiquitin-mediated proteasome system (UPS) and autophagy.  Proteins can be targeted for degradation by their N-terminal amino acid which can be modified to become an N-degron.  N-degrons allow for selective degradation first through the UPS, however, if the proteasome is not highly functional, these proteins may be degraded via autophagy, a lysosomal mediated form of proteolysis 1. While many studies have shown that...

Application Focus: New Methods for iPSC Differentiation, Inducing a Mammary Fate

Monday, February 12, 2018 - 15:51
Lactalbumin Antibody Immunohistochemistry Paraffin NBP1-87715

Discovery of the Key to Pluripotency

Induced pluripotent stem cells (iPSCs) may be generated from a wide range of fully differentiated cells, and under optimal conditions may be prompted to differentiate into virtually any fate. Induced stem-like cells not only provide an alternative to embryonic stem cells, but more importantly represent powerful tools for drug development and disease modeling.1

Methods for the induction of pluripotency were developed in 2006, when genes critical for cellular reprograming were identified by Yamanaka and Takahashi, including OCT4, SOX2,...

Stemness for Surviving Hypoxia: TGF-beta/Smad Signaling in Multiple Myeloma

Tuesday, February 6, 2018 - 13:06
TGF-B Pathway

By Jamshed Arslan Pharm.D.

Multiple myeloma (MM) is a cancer of antibody-producing plasma cells. The bone marrow (BM) of MM patients is hypoxic, and MM cells overexpress many cancerous genes that are regulated by hypoxia-inducible factors (HIFs). Cancer stem cells (CSCs) in the hypoxic BM regions are blamed for the incurability of MM, because CSCs are often resistant to drugs currently used against BM cancers (including proteasome inhibitors and immunomodulatory agents). Dr. Eishi Ashihara at the Kyoto Pharmaceutical University, Japan, and colleagues, set out to characterize the biology of MM stem cells. They found that TGF-beta...

CaMKII stimulates autophagic degradation of 'ID', a new frontier against cancer

Tuesday, January 30, 2018 - 13:32
A-Phagy f2 - molecular machinery

By Yoskaly Lazo-Fernandez, PhD

The field of Cancer Stem Cell (CSC) research has been gaining traction in recent years1. CSCs are a minority group of cells (usually about 1 in 10000) within solid tumors of hematological cancers, which possess similar characteristics to normal stem cells. It is believed that these cells, which are identified by markers usually only found on tissue stem cells, are the only cancerous cells that can induce tumor development and propagation or metastasis2. Consequently, gaining a better understanding of the molecular machinery...

Characterization of Stress-Related Deamidation in Therapeutic Proteins

Tuesday, January 23, 2018 - 15:02

Therapeutic proteins such as monoclonal antibodies (mAbs) can be subject to physical or chemical stress during the manufacturing process and supply chain. A common chemical degradation is the deamidation of the amino acid asparagine to aspartic acid or iso-aspartic acid. Modification of glutamine to glutamic acid is also possible, although this occurs at a slower rate. When deamidation occurs in the antigen binding region of the mAb, it can result in a loss of potency. This sequence liability may be defined as a critical quality attribute and represents a risk to the development of novel biologics and biosimilars alike.  As such, it is important to have reliable protein characterization methods with sufficient sensitivity and selectivity to identify and quantify levels of deamidation.

Physicochemical analysis

The transformation of an amide side-chain, via a succinimide intermediate, to a carboxylic acid results in a change in the net charge of the...

Marked for Deletion: Parkin Ubiquitinylates HIF-1α to Stop Cancer

Tuesday, January 23, 2018 - 08:17
Parkin Ubiquitinylates HIF-1 alpha

By Jamshed Arslan Pharm.D.

Parkin got its name from Parkinson’s disease (PD). Being an E3 ubiquitin ligase enables Parkin to ubiquitinate and degrade proteins involved in PD (such as CDCrel-1, α-synuclein, and synphilin-1). Now we know that mutations in the Parkin gene (PARK2) can not only lead to a hereditary form of PD, but may also make people prone to various malignancies including breast cancer. Hypoxia-inducible factor-1α (HIF-1α), which adapts cells to hypoxic conditions in...

Brain size matters: MTOR regulates autophagy and number of cortical interneurons

Tuesday, January 16, 2018 - 09:08
MTOR and autophagy

By Jamshed Arslan Pharm.D.

Interneurons transmit impulses between other neurons, in part, to facilitate the birth of neurons. Cortical interneurons themselves arise from the progenitors in the ventral telencephalon, a brain region that generates basal ganglia. The role of mechanistic target of rapamycin (MTOR) signaling in this process is poorly understood, even though MTOR is known to determine brain size. By deleting Mtor in mouse interneuron progenitors and their progeny, Dr. Woo-Yang Kim’s team at the University of Nebraska Medical Center, USA, found two homeostatic activities of MTOR in the developing brain: regulation of autophagy and...

Chaperone Mediated Autophagy (CMA) does it all!

Tuesday, January 9, 2018 - 11:01
HSPA8/HSC71/HSC70 Antibody

By Christina Towers, PhD.

The degradation of cellular proteins is a critical step of both regulation and quality control and results in the turn over and recycling of critical amino acids. The two main mechanisms of protein degradation converge on either the proteasome or the lysosome, the latter of which can be further subdivided into macroautophagy, microautophagy, and chaperone mediated autophagy.

 Macroautophagy is the...

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