Two different tumour-necrosis factors (TNFs), first isolated in 1984, were found to be cytotoxic to tumour cells and to induce tumour regression in mice. Research during the past two decades has shown the existence of a superfamily of TNF proteins consisting of 19 members that signal through 29 receptors. These ligands, while regulating normal functions such as immune responses, haematopoiesis and morphogenesis, have also been implicated in tumorigenesis, transplant rejection, septic shock, viral replication, bone resorption, rheumatoid arthritis and diabetes; so indicating their role as 'double-edged swords'. These cytokines either induce cellular proliferation, survival, differentiation or apoptosis. Blockers of TNF have been approved for human use in treating TNF-linked autoimmune diseases in the United States and other countries.

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Signalling pathways of the TNF superfamily: a double-edged sword.

Apoptosis: a link between cancer genetics and chemotherapy.

Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, γ-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.

Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

The RB and p53 pathways in cancer

Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage. Death receptors — members of the tumour-necrosis factor receptor (TNFR) superfamily — signal apoptosis independently of p53. Decoy receptors, by contrast, are a non-signalling subset of the TNFR superfamily that attenuate death-receptor function. Agents that are designed to activate death receptors (or block decoy receptors) might therefore be used to kill tumour cells that are resistant to conventional cancer therapies.

Targeting death and decoy receptors of the tumour-necrosis factor superfamily

Polyethylene glycol modified FGF21 engineered to maximize potency and minimize vacuole formation.

Background: Preclinical efficacy and safety studies, especially chronic studies, can be difficult to perform when the candidate therapeutic agent is a human protein due to the specificity of these molecules for the human target. The main issues are: i) the human protein or target may not be pharmacologically active in rodents or dogs, the standard toxicology species; or ii) the therapeutic agent may be so immunogenic in these species, that longer duration studies are not possible due to the formation of neutralizing antibodies. Thus, preclinical safety testing of biotherapeutics poses a particular challenge in selecting a relevant animal species for use in toxicology studies. Objective: This article will discuss the considerations that are unique to safety assessment of biotherapeutics and will provide alternatives to the standard toxicity testing which is conducted for small molecules. Methods: This article is based on published information with regards to species selection considerations as well as info...

Species selection considerations for preclinical toxicology studies for biotherapeutics.

Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period ☆

High titer (>10 g/L) monoclonal antibody (mAb) cell culture processes are typically achieved by maintaining high viable cell densities over longer culture durations. A corresponding increase in the solids and sub-micron cellular debris particle levels are also observed. This higher burden of solids (≥15%) and sub-micron particles typically exceeds the capabilities of a continuous centrifuge to effectively remove the solids without a substantial loss of product and/or the capacity of the harvest filtration train (depth filter followed by membrane filter) used to clarify the centrate. We discuss here the use of a novel and simple two-polymer flocculation method used to harvest mAb from high cell mass cell culture processes. The addition of the polycationic polymer, poly diallyldimethylammonium chloride (PDADMAC) to the cell culture broth flocculates negatively-charged cells and cellular debris via an ionic interaction mechanism. Incorporation of a non-ionic polymer such as polyethylene glycol (PEG) into the...

https://www.tandfonline.com/doi/pdf/10.1080/19420862.2015.1007824

PDADMAC flocculation of Chinese hamster ovary cells: Enabling a centrifuge-less harvest process for monoclonal antibodies

Receptor activator of NF-κB (RANK) and its ligand (RANKL) are essential for osteoclast formation, function, and survival Osteoprotegerin (OPG) inhibits RANK signaling by sequestering RANKL This study evaluated the antiosteoclast and immunoregulatory effects of mouse rRANK-Fc, which, similar to OPG, can bind RANKL The effect of RANKL inhibition by RANK-Fc on osteoclast function was determined by inhibition of vitamin D3 (1,25(OH)2D3)-induced hypercalcemia Mice were injected with a single dose of 0, 10, 100, 500, or 1000 μg of RANK-Fc; 100 μg of OPG-Fc; or 5 μg of zoledronate 2 h before 1,25(OH)2D3 challenge on day 0, and sacrificed on days 1, 2, 4, 6, 8, 12, 16, and 20 RANK-Fc doses of 100 or 500 μg were tested in a mouse respiratory influenza virus host-resistance model A single dose of RANK-Fc ≥100 μg suppressed elevation of serum calcium levels and suppressed the bone turnover marker serum pyridinoline at day 4 and later time points, similar to those observed with OPG-Fc and zoledronate (p ≤ 001 vs controls) By day 6, both immature and mature osteoclasts were depleted by high doses of RANK-Fc (500 and 1000 μg) or 100 μg of OPG-Fc RANK-Fc doses of 100 or 500 μg had no detectable effect on immune responses to influenza infection, as measured by activation of cytotoxic T cell activity, influenza-specific IgG response, and virus clearance RANK-Fc inhibition of RANKL has antiosteoclast activity at doses that have no detectable immunoregulatory activity, suggesting that RANKL inhibitors be further studied for their potential to treat excess bone loss

Receptor Activator of NF-κB Ligand Inhibition Suppresses Bone Resorption and Hypercalcemia but Does Not Affect Host Immune Responses to Influenza Infection

Jeanine L. Bussiere

Papers

Polyethylene glycol modified FGF21 engineered to maximize potency and minimize vacuole formation.

Species selection considerations for preclinical toxicology studies for biotherapeutics.

Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period ☆

PDADMAC flocculation of Chinese hamster ovary cells: Enabling a centrifuge-less harvest process for monoclonal antibodies

Receptor Activator of NF-κB Ligand Inhibition Suppresses Bone Resorption and Hypercalcemia but Does Not Affect Host Immune Responses to Influenza Infection