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In Vivo Model on Primates Gene Therapy (2002) 9, 282–290 2002 Nature Publishing Group All rights reserved 0969-7128/02 $25.00 www.nature.com/gt RESEARCH ARTICLE Antibody-mediated lung endothelium targeting: in vivo model on primates IV Balyasnikova1, DC Yeomans2, TB McDonald1 and SM Danilov1 1Department of Anesthesiology, University of Illinois at Chicago, IL, USA; and 2Department of Anesthesia, Stanford University, Palo Alto, CA, USA We have recently provided evidence that angiotensin-con- MAb i2H5, which binds to macaque ACE with substantially verting enzyme (ACE) is a rational target and anti-ACE higher affinity than mAb 9B9, also more effectively accumu- monoclonal antibodies (mAbs) are suitable molecules for lates in their lungs than mAb 9B9. Immunospecificity of lung directing gene/drug delivery into the pulmonary endothelium accumulation (mAb/control IgG ratio) was 37 for i2H5 and of rodents. As a step towards gene therapy clinical trials 0.5 for 9B9. Lung selectivity of i2H5 uptake (lung/blood ratio) using this approach, the present study evaluated the poten- was around 10. Therefore mAb i2H5 may be useful for in tial of anti-ACE mAbs for in vivo lung endothelium targeting vivo lung targeting in non-human primates, whereas 9B9 in 10 species of primates. Cross-reactivity of 10 distinct may be most useful in primates that are closer to humans mAbs directed to human ACE with ACE from baboon, (chimpanzee). A combination of these two mAbs may be macaques, cercopithecus and chimpanzee revealed that the particularly useful for human clinical trials of gene/drug ther- highest binding with ACE from baboon and macaques was apy for lung disorders such as pulmonary hypertension and with mAb i2H5, from chimpanzee – mAb 9B9, and from lung metastases. human – 9B9 and i2H5. Thereafter, in vivo biodistribution of Gene Therapy (2002) 9, 282–290. DOI: 10.1038/sj/gt/3301657 mAbs i2H5 and 9B9 was estimated in Macaca arctoides. Keywords: pulmonary endothelium; angiotensin-converting enzyme; monkey; monoclonal antibodies; gene delivery Introduction injury induced by hydrogen peroxide by the systemic mAb 9B9 conjugated with catalase.14 The angiotensin-converting enzyme (ACE, kininase II, This anti-ACE mAb was successfully used to increase CD143), an important regulator of vascular tone and selectivity and efficacy of transgene expression that have 1,2 remodeling, is expressed on the luminal surface of been incorporated into viral vectors. Thus, using a bispe- 3–6 endothelial cells of different types of blood vessels. The cific conjugate approach for direction of adenoviruses to unique tissue distribution of endothelial ACE, along with ACE, we achieved dramatically (20-fold) enhanced pul- 5,6 preferential expression in lung capillaries, also makes monary gene delivery and expression in vivo along with it an almost ideal target for therapy directed toward significantly reduced (five- to eight-fold) transgene pulmonary endothelium. expression in non-targeted organs in rats.15 Moreover, the Previous studies from our group demonstrated that combination of transductional retargeting adenoviruses monoclonal antibodies directed toward ACE may be (via ACE) and transcriptional retargeting (with the use of highly efficient and specific carriers for the delivery of an endothelial specific promoter for vascular endothelial therapeutic substances (isotopes, proteins, drugs) to the growth factor receptor 1, flt-1) resulted in a remarkable 7–10 lung vasculature. For example, we have shown that (300 000-fold), highly synergistic improvement in selec- after systemic injection, an anti-ACE monoclonal anti- tivity of transgene expression for lung compared with the body (designated 9B9) selectively accumulates in the usual site of vector sequestration, the liver.16 8,11 10 lungs of several mammals, including humans. Fur- The antibody-directed lung-selective in vivo gene deliv- thermore, systemic administration of mAb 9B9 that had ery system via ACE shows great potential in the rat.15,16 been conjugated to the plasminogen activators, catalase However, before this method can be applied to human or superoxide dismutase, results in the specific targeting clinical trials, this work must better approach the human and prolonged association of these drugs with the pul- condition. As recently reviewed by Donahue and Dun- 12,13 monary vasculature of rats. These conjugates retain bar,17 despite success in usual laboratory models on rod- biological activity and demonstrate therapeutic effects. ents and in vitro, ‘the unique predictive value of nonhu- For example, rat lung endothelium was protected from man primate models … has become more apparent, and major advances in gene transfer efficiency have been made utilizing these powerful, but expensive and com- Correspondence: SM Danilov, Anesthesiology Research Center, Univer- sity of Illinois at Chicago, 1819 W Polk Street (M/C 519), Chicago, IL plex systems’. The distinctions between primates and 60612, USA; [email protected] rodents can dramatically impact on the predictive value Received 10 July 2001; accepted 17 December 2001 of gene transfer trials in mice and rats for clinical applica- bility.17,18 The work presented here clearly bears this out. Lung endothelium targeting in primates IV Balyasnikova et al 283 Thus, this study focused on the ability of several mAbs was intermediate between human and rat. ACE activity directed against different epitopes of human ACE, to tar- was much higher in the kidney of studied animals rela- get lung endothelium in primates, and thus for delivery tive to lung tissue or in serum. The observed high ACE of transgenes to the pulmonary endothelium. This in vivo level in the kidney appears to conflict with the absence model performed in both rats and non-human primates of mAb 9B9 in kidney after in vivo antibody injection in should prove helpful in the pursuit of human clinical all animals studied previously.6–10 However, in the kid- studies. ney, ACE is most highly expressed in the epithelium of proximal tubules and is found as well in brush border of Results and discussion intestine.19 Thus, both of these areas are essentially inac- cessible to monoclonal antibodies in circulation.6–13 20–22 Tissue and plasma ACE activity in primates It is likely that the large endothelial surface area, This study was designed to develop an in vivo model for and the consequent high ACE levels in the lung contrib- utes to the selective accumulation of anti-ACE mAbs in ACE-dependent drug/gene delivery to the pulmonary 6–13 endothelium of primates. As we have previously demon- the lung endothelium after systemic injection. Another strated, anti-ACE mAb 9B9 specifically accumulates in contributing factor to this accumulation is the hetero- the rat, hamster and cat lungs after systemic injection due geneous distribution of ACE in human and rat endo- to a high concentration of ACE in the lungs of these spec- thelial cells along the vascular tree. On average, only 10– ies.11 However, data have not yet been described for ACE 20% of human and rat capillary endothelial cells in sys- activity in tissues and blood of primates. temic circulation demonstrate ACE expression; whereas, Data on ACE activity in plasma, lung and kidney of virtually all endothelial cells in pulmonary capillaries 5,6 baboon (Papio anubis), macaques (Macaca arctoides, Macaca strongly express ACE. This finding explains why mulatta, Macaca fascicularis, Macaca nemestrina, Macaca among several anti-endothelial mAbs studied (ICAM-1 assamensis, Macaca fuscata), cercopithecus (Cercopithecus (CD-54), PECAM (CD-31), Thy.1.1 (CD-90), ACE (CD- aethiops), as well as chimpanzee (Pan troglodytes) are 143)), anti-ACE mAbs demonstrated the most selective presented in Table 1. ACE activity in the lung of these lung accumulation after systemic injection.6 The selec- species was between three and eight times higher than tivity of ACE expression in the lung appears to be fairly in human, but between three and 10 times lower than in ubiquitous across mammals, as we have observed a simi- rat lung. It is likely that not only the absolute content of lar pattern of ACE expression in pulmonary versus sys- ACE in the lung, but also the gradient of ACE concen- temic circulation across all 26 species tested, including tration from lung to blood (the organ/blood ACE ratio) human and non-human primates (Franke et al, in determines the efficacy and selectivity of antibody lung preparation). accumulation.11 These data also show that the Therefore, the common cross-species character of endo- tissue/serum ACE activity ratio in non-human primates thelial ACE distribution pattern (Refs 5 and 6, and Franke Table 1 ACE activity in tissues from different animal species Animal Tissue ACE activity Tissue/plasma (units/g tissue) ratio Human Homo sapiens Plasma 0.028 ± 0.01 1 Lung 0.52 ± 0.03 19 Kidney 2.34 ± 0.06 84 Chimpanzee Pan troglodytes Plasma 0.020 ± 0.004 1 Baboon Papio anubis Plasma 0.102 ± 0.001 1 Lung 4.2 ± 0.59 41 Kidney 13.6 ± 3.4 133 Macaque Stump tail/Bear macaque Plasma 0.046 ± 0.014 1 Macaca arctoides Lung 1.34 ± 0.51 29 Kidney 12.1 ± 1.2 263 Rhesus macaque Plasma 0.090 ± 0.01 1 Macaca mulatta Lung 4.3 ± 0.5 48 Kidney 5.6 ± 0.6 62 Cynomolgus macaque Plasma 0.054 ± 0.006 1 Macaca fascicularis Lung 5.56 ± 0.42 103 Kidney 4.83 ± 0.58 86 Japanese Snow macaque Plasma 0.087 ± 0.005 1 Macaca fuscata Lung 5.0 ± 0.204 57 Kidney 9.0 ± 0.8 104 Assam macaque Macaca assamensis Plasma 0.048 ± 0.01 1 Pigtail macaque Macaca nemestrina Plasma 0.075 ± 0.02 1 Cercopithecus African Green Monkey Cercopithecus aethiops Plasma 0.048 ± 0.006 1 Rat Sprague–Dawley rat Plasma 0.262 ± 0.014 1 Rattus norvegicus Lung 13.5 ± 0.62 52 Kidney 0.25 ± 0.05 1 The plasma, kidney and lung tissues were prepared as described in Materials and methods.
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