Paul K. Ng

Antifibrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver fibrosis in rats.

Liver fibrosis is characterized by increased synthesis, and decreased degradation, of extracellular matrix (ECM) within the injured tissue. Decreased ECM degradation results, in part, from increased expression of tissue inhibitor of metalloproteinase‐1 (TIMP‐1), which blocks matrix metalloproteinase (MMP) activity. TIMP‐1 is also involved in promoting survival of activated hepatic stellate cells (HSCs), a major source of ECM. This study examined the effects of blocking TIMP‐1 activity in a clinically relevant model of established liver fibrosis. Rats were treated with carbon tetrachloride (CCl4), or olive oil control, for 6 weeks; 24 days into the treatment, the rats were administered a neutralizing anti–TIMP‐1 antibody derived from a fully human combinatorial antibody library (HuCAL), PBS, or an isotype control antibody. Livers from CCl4‐treated rats exhibited substantial damage, including bridging fibrosis, inflammation, and extensive expression of smooth muscle α‐actin (α‐SMA). Compared to controls, rats administered anti–TIMP‐1 showed a reduction in collagen accumulation by histological examination and hydroxyproline content. Administration of anti–TIMP‐1 resulted in a marked decrease in α‐SMA staining. Zymography analysis showed antibody treatment decreased the activity of MMP‐2. In conclusion, administration of a TIMP‐1 antibody attenuated CCl4‐induced liver fibrosis and decreased HSC activation and MMP‐2 activity. (HEPATOLOGY 2004.)

Optimization of Solute Separation by Diafiltration

Abstract Preliminary consideration suggests that process time in diafiltration can be optimized. A mathematical derivation of the optimum time gives a surprisingly simple general relationship between the bulk concentration and the membrane surface concentration. Experimental values confirm that an optimum value can indeed be obtained.

Plasma protein fraction. Product improvement studies.

The vasodilative effects associated with the use of sodium acetate have been reported in the literature. Preparations of plasma protein fraction (PPF) substantially free of this vasodilator were developed. This paper presents and discusses experimental work on the improved product.

Process-scale purification of immunoglobulin M concentrate.

An IgM concentrate was purified from Cohn fraction III. Efficiency of euglobin precipitation was shown to be controlled by pH and ionic strength. Prekallikrein activator activity in the product was insignificant. Overall yield from the octanoic acid supernate and purity of the concentrate were 66 ± 8 (n = 16) and 50 ± 5% (n = 16), respectively. Solvent‐detergent treatment to inactivate lipid‐enveloped viruses was demonstrated and implemented into the process. Process studies to control residual virucidal agents and C4a generating activity are presented.

Tangential Flow Cell Separation from Mammalian Cell Culture

Abstract Tangential flow cell separation from fermenter-derived mammalian cell culture has been studied. The process is governed by transmembrane pressure and interactions of carry-over cells with the membrane. Membrane regeneration and comparison with other cell separation systems were discussed. Higher throughput per unit area over conventional dead end filter was demonstrated.