Antibody News

By Christina Towers, PhD.

MAPK Signaling and Disease

Mitogen-activated protein kinases (MAPKs) are serine-threonine kinase signaling molecules that function in a variety of cellular processes including cell differentiation, proliferation, survival, death, and transformation.  In mammals, there are 3 subfamilies of MAPKs including ERK, p38, and c-Jun each containing multiple isoforms. The MAPK signaling cascade is mediated by an upstream MAP3K which phosphorylates and activates a MAP2K which in turn activates a...

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, A_2A receptor (A_2AR), 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...

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...

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),...

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...

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...

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 binding of an antigen to the scFv.

CAR-T therapy has...

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...

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 amount of full...

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...

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...

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...