For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, developing two separate monoclonal antibodies for clinical use as combination therapy is impractical, owing to regulatory hurdles and cost. Multi-specific, antibody-based molecules have been investigated; however, their therapeutic use has been hampered by poor pharmacokinetics, stability and manufacturing feasibility. Here, we describe a generally applicable model of a dual-specific, tetravalent immunoglobulin G (IgG)-like molecule--termed dual-variable-domain immunoglobulin (DVD-Ig)--that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies. This molecule can be efficiently produced from mammalian cells and exhibits good physicochemical and pharmacokinetic properties. Preclinical studies of a DVD-Ig protein in an animal disease model demonstrate its potential for therapeutic application in human diseases.

The effect of fish meal (FM) substitution with fermented soybean meal (FSBM) in the diets of the carnivorous marine fish, black sea bream, Acanthopagrus schlegelii, was investigated. An 8-wk feeding trial was conducted with black sea bream (11.82 ± 0.32 g; mean initial weight) in indoor flowthrough fiberglass tanks (25 fish per tank). Six isonitrogenous and isoenergetic diets were formulated, in which FM was replaced by FSBM at 0% (control diet), 10% (FSBM10), 20% (FSBM20), 30% (FSBM30), 40% (FSBM40), or 50% (FSBM50), respectively. Each diet was fed to triplicate groups of fish twice daily to apparent satiation. The results showed that there was no difference in survival of black sea bream during the feeding trial. Fish fed the FSBM10 or FSBM20 diet showed comparable growth performance compared with fish fed the control diet (P > 0.05), whereas more than 30% replacement of FM adversely affected weight gain and specific growth rate (P < 0.05). Feed intake was significantly lower for fish fed the FSBM50 diet compared with fish fed the control diet. Feed conversion ratio (FCR) tended to increase with increasing dietary FSBM with the poorest FCR observed for fish fed the FSBM50 diet. Protein efficiency ratio and protein productive values showed similar patterns. Apparent digestibility of nutrients significantly decreased with increasing dietary FSBM level. With the exception of protein content, no significant differences in whole body and dorsal muscle composition were observed in fish fed the various diets. Fish fed the FSBM50 diet had significantly lower intraperitoneal ratio than fish fed the control or FSBM10 diet. Hepatosomatic index and condition factor were unaffected by dietary treatments. This study showed that up to 20% of dietary FM protein could be replaced by FSBM protein in the diets of juvenile black sea bream.

Signal transduction through the interleukin-1 receptor (IL-1R) pathway mediates a strong pro-inflammatory response, which contributes to a number of human diseases such as rheumatoid arthritis. Within the IL-1 family, IL-1alpha and IL-1beta are both agonistic ligands for IL-1R, whereas IL-1 receptor antagonist (IL-1ra) is an endogenous antagonist that binds to IL-R, but does not signal. Therefore, the ideal therapeutic strategy would be blocking both IL-1alpha and IL-1beta, but not IL-1ra. However, due to low sequence homology between the three members of the family, it has been exceedingly difficult to identify potent therapeutic agents, e.g., monoclonal antibodies (mAbs), that selectively recognize both IL-1alpha and IL-1beta, but not IL-1ra. Currently, several anti-IL-1 therapeutic agents in clinical development either inhibit only IL-1beta (i.e., anti-IL-1beta mAb), or recognize all three ligands (i.e., anti-IL-1R mAb or IL-1R Trap). We have recently developed a novel dual variable domain immunoglobulin (or DVD-Ig) technology that enables engineering the distinct specificities of two mAbs into a single functional, dual-specific, tetravalent IgG-like molecule. Based on this approach, we have developed anti-human IL-1alpha/beta DVD-Ig molecules using several pairs of monoclonal antibodies with therapeutic potential, and present a case study for optimal design of a DVD-Ig agent for a specific target pair combination.

An 8-week feeding trial was conducted to determine the dietary arginine requirement of juvenile black sea bream Sparus macrocephalus in 18 350 L indoors £ow-through circular ¢breglass tanks. Six isonitrogenous and isoenergetic diets were formulated to contain graded levels of L-arginine (1.85%, 2.23%, 2.51%, 2.86%,3.20% and 3.46% dry diet) from dietary ingredients and crystalline arginine. Each diet was randomly assigned to triplicate groups of 25 juvenile ¢sh (10.51 AE 0.15 g) twice daily (08:00 and 16:00 hours) to apparent satiation. Results showed that the speci¢c growth rate (SGR) increased with increasing dietary arginine levels up to 2.51% and remained nearly the same thereafter. Feed e⁄ciency ratio, protein e⁄ciency ratio (PER) and protein productive value all showed an increasing tendency and then levelled o¡. Apparent digestibility coe⁄cients of dry matter, crude protein and gross energy signi¢cantly improved up to 2.86% arginine diet and decreased at di¡erent extents thereafter. Fish fed 1.85% arginine diet had signi¢cantly lower protein content in the whole body and dorsal muscle than those fed diets supplemented with or 42.86% of arginine. Lipid content decreased and lower value occurred at 3.46% of dietary arginine. The dietary essential amino acid composition in the whole body of the black sea bream was signi¢cantly in£uenced by dietary arginine. Arginine retention increased with an increasing dietary arginine level from 1.85% to 3.20%, then declined slightly at 3.46% arginine diet. Serum biochemical parameters were signi¢cantly a¡ected by the dietary arginine level except for the cholesterol content. Broken-line regression based on SGR and second-order polynomial regression based on PER indicated that the optimum dietary arginine requirements for juvenile black sea bream were 2.79% and 3.09% diet, corresponding to 7.74% and 8.13% of the dietary protein respectively. , 320 and p-aminobenzoic acid, 50. zOthers (%) : carboxymethylcellulose, 4; sodium dihydrogen phosphate, 2.5; k-carrageenan, 2.5; a-cellulose, 5.08; betaine, 0.3; Cr 2 O 3 , 0.5. ‰Values for the proximate analysis of the test diets are means of triplicate analyses. Optimum arginine requirement of black sea bream F Zhou et al. Optimum arginine requirement of black sea bream F Zhou et al. r 2010 The Authors Aquaculture Research r 2010 Blackwell Publishing Ltd, Aquaculture Research, 41, e418^e430 e421 Ã Values are presented as mean AE SD (n 5 3); values with di¡erent superscripts in the same row di¡er signi¢cantly (Po0.05).Survival (%) 5 100 Â ¢nal ¢sh number/initial ¢sh number; WG (weight gain) (%) 5 100 Â (FBWIBW)/IBW; SGR (speci¢c growth rate) (% day À 1 ) 5 100 Â (ln FBWln IBW)/day; CF (condition factor) (g cm À 3 ) 5 100 Â (live weight, g)/(body length, cm) 3 ; HSI (Hepatosomatic index) 5 100 Â (liver weight, g)/(body weight, g); FER (feed e⁄ciency ratio) 5 100 Â wet weight gain in g/dry diet fed in g; PER (protein e⁄ciency ratio) 5 weight gain in g/protein intake in dry basis in g; PPV (protein productive value) 5 g protein gain/g pr...