Abcream

A topical treatment of psoriasis with monoclonal antibodies that neutralize interleukin 8 (IL-8)
1. Introduction:

Psoriasis is a chronic, inflammatory dermatitis induced by multiple factors that affects people with a specific genetic background. The incidence of the disease varies by population. According to the National Institute of Health (NIH), approximately 2.2% of the United States population is affected by psoriasis. Internationally, the incidence of psoriasis is approximately 120-180 million people. The rates of incidence for various nations/regions are as follows: Scandinavia 7-8%Denmark 5-6%Germany 4%Canada 2-3%Russia 2-3%Northern Europe 2-3%Great Britain 2%China 0.47%and Kuwait 0.11%. It is interesting to note that the more developed the country, the higher percentage of people affected by psoriasis. About 4% of the population in the most developed countries suffers from psoriasis. Some exceptions are Japan and Australia. The etiology of psoriasis might involve the over-expression of a number of cytokines, among which Interleukin-8 (IL-8) plays a pivotal role. Research has shown that IL-8 levels could elevate 100-fold in psoriasis-affected tissue when compared to normal skin tissue. In addition to contributing to the inflammation process, IL-8 is also a growth factor for skin cells that proliferate in psoriatic tissue. Finally, IL-8 is a potent angiogenesis factor, so it may contribute to the ingrowth of blood vessels that nourish psoriatic tissue. Based on these findings, Anogen-Yes Biotech Laboratories Ltd. was the first company in the world to carry out the research and development of the revolutionary anti-IL-8 treatment of psoriasis in 1993. Abcream (Anti-IL-8 monoclonal antibody topical cream) reverses the inflammatory pathological changes by neutralizing the excessive IL-8 in the psoriatic tissue and other skin conditions. 2. The pharmacological mechanism 2.1. The biological functions of interleukin-8 (IL-8): Interleukin-8IL-8) is a member of the chemokine superfamily with 72 residues (MW=8,000). Interleukin-8 has been cited as a pro-inflammatory mediator in gingivitis and psoriasis. IL-8 acts as neutrophil activator and chemotactic factor. In particular, there is compelling evidence showing that IL-8 plays a pivotal role in the inflammatory process. IL-8 is secreted by several cell types, including macrophage, neutrophil, monocyte, endothelial cells, keratinocyte etc., and affects the cells to induce inflammatory response. Most likely, the effect of IL-8 in promoting or causing tissue damage is by inducing the infiltration of neutrophilic leukocytes as well as by triggering the release of lysosomal enzymes and superoxide anions from leukocytes. The excess amount of IL-8 level in affected tissues
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has been found to be associated with a number of disease states. Among these diseases are psoriasisarthritis deformans, idiopathic fibrosis of the lung, enteritisadult respiratory distress syndrome, and septic shock etc. 2.2. The association of IL-8 over expression with psoriasis: Psoriasis is characterized by abnormal keratinocyte growth and differentiation. The functional abnormality of keratinocytes is believed to be triggered by T lymphocytes, and various cytokines. In addition, polymorphonuclear neutrophil (PMN) infiltration of the skin and Munro microabscesses are characteristic histological findings in psoriasis, confirming that neutrophils have a role in the pathogenesis of this disease. It has been postulated that in addition to influencing keratinocyte growth and differentiation of neutrophils in the epidermis, IL-8 might also trigger T-lymphocyte activation by inducing cell-surface expression of HLA-Dr. The accumulation of neutrophils in the outermost layer of the epidermis has been associated with the presence of highly inflammatory, treatment-refractory psoriasis plaques. IL-8 plays a crucial role in the pathogenesis of psoriasis: 2.2.1. IL-8 is a strong chemotactic factor. IL-8 over-expression in the skin gathers large amount of neutrophils, T-lymphocytes and other inflammatory cells. The infiltration of these cells damages skin tissue and causes blisters. The gathered neutrophils and T-lymphocytes also produce large amount of IL-8 and aggravate local pathological changes, resulting in inflammation of skin and accumulation of debris and scales formed by necrotic cells and dead tissue. IL-8 is a strong growth factor of epidermal cells. Excessive amount of IL-8 production can lead to the overgrowth of abnormal keratinocytes in the focus of psoriasis. IL-8 is also a potent angiogenesis factor. It causes the acceleration of blood vessel formation in psoriatic focus, making possible sufficient blood supply for the abnormal growth and proliferation of epidermal cells. The biological effect of IL-8 is mediated by its receptors on the surface of the inflammatory cells. Both keratinocyte in the focal zone and the infiltrated neutrophilic leukocyte can express large amount of IL-8 receptors on their surface. Increased numbers of IL-8 receptors and elevated IL-8 can lead to severe dermatitis in the vicious cycle.

2.2.2.

2.2.3.

2.2.4.

2.3. The therapeutic effects of anti-human IL-8 monoclonal antibody on psoriasis: The monoclonal antibody is a high titer neutralization antibody specific to IL-8. It can make an effective therapy to psoriasis by neutralizing excessive IL-8 production and eliminating neutrophil recruitment, thus, possessing anti-inflammatory role at the psoriatic skin. In addition, the antibody can block IL-8s angiogenic effect. Therefore, local microvascular formation and the abnormal proliferation, differentiation, and necrosis of keratinocytes can be controlled. As a total result, the symptoms of psoriasis can be reduced.

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2.4. The Specificity of this anti-IL-8 monoclonal antibody: The specificity of this anti-IL-8 antibody was tested by measuring the cross-reactivity of this antibody with other cytokines, chemotactic factors and cytokines that share structural similarity with IL-8. The results (Table 1 & 2) showed that the anti-IL-8 monoclonal antibody was highly specific to IL-8, and had no cross-reactivity with following factors: GM-CSF, TGF-, MCAF, TNF-, IL-7, IL-1, b-FGF, IL-16, MCP-3, M-CSF, EGF, and GRO, PF-4, ENA78, GCP2. The following results were from 2 ELISA assays:

Table 1.

Test the cross-reactivity with other cytokines and chemotactic factors. Cytokine IL-8 GM-CSF TGF- MCAF TNF- IL-7 IL-1 b-FGF IL-16 MCP-3 MCSF EGF BSA HAS OD reading Over reading range (>2.7) 0.037 0.021 0.023 0.039 0.060 0.029 0.027 0.044 0.024 0.044 0.044 0.147 0.129

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Table 2.

Test the cross-reactivity with structurally similar cytokines: Cytokine IL-8 GROa PF-4 ENA78 NAP-2 GCP-2 OD reading Over reading range (>2.7) 0.097+ 0.008 0.113 + 0.04 0.073 +0.009 0.031 +0.004 0.088 +0.007

2.5. Neutralizing the chemotactic effect of IL-8 in vitro Chemotaxis assay was used to determine the neutralization effect of anti-IL-8 antibody to the IL-8 induced chemotactic migration of IL-8 receptor expressing 293 cells. Method: 10ng/ml IL-8 antigen was used to react with anti-IL-8 monoclonal antibody diluted to different concentrations (50g/ml, 5g/ml, 0.5g/ml, and 0.05g/ml). For negative control, only antigen existed in the reaction. All the samples were reacted at 37C for 30mins. Each sample was seeded respectively into the wells at the lower layer of the chemotaxis chamber. 50l of cell culture was seeded into each well at the upper layer of the chamber. Between upper and lower layer of wells, 10m pore-size polycarbonate ester filter membrane was used to separate the two layers. The chamber was incubated in 5 % CO2 at 37C for 5 hours. After that, the filter membrane was taken out and stained with Dieff-Quick. The number of cells on the membrane was counted and the result was calculated by the average cell numbers of three wells. The data (Table 3) below showed that this anti-IL-8 monoclonal antibody strongly inhibited the chemotactic migration of 293 cells by neutralizing IL-8.

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Table 3.

Inhibition of the chemotactic migration of 293 cells by IL-8 antibody. Anti-IL-8 antibody 50g/ml 5g/ml 0.5g/ml 0.05g/ml IL-8 antigen 10ng/ml Ratio of antibody to antigen 5000:1 500:1 50:1 5:1 Inhibition in chemotaxis 118.25% 99.81% 83.90% 17.09%

% Inhibition in chemotaxis = 1 (the number of migrated cells in anti-IL-8 group the number in medium control group) / (the number of migrated cells in IL-8 group the number in medium control group). 2.6. Cytokine profile in the skin tissue of psoriasis patients 2.6.1. Material and method: 2.6.1.1. Patients: 11 patients with active plaque-type psoriasis (male: 6, female: 5, the median age was 39.2, and the age span was 21~68) were selected for this study. The conditions of these psoriasis patients were determined by the same clinical doctor on the standard of PASI. The median of the conditions was 18.6, and the span was 5.7~34.6. All of them didnt have any neopathy or received treatment 21 days prior to the experiment. The control group was 8 normal volunteers (male: 4, female: 4, the median age was 40.5, and the age span was 22~64). 2.6.1.2. Biopsy and organ culture: 40mm2 biopsy skin samples were collected from the lesion region and the surrounding non-inflammatory skin of the patients (at least 10cm away from the lesion), and the healthy skin tissue were collected from the normal volunteers as control. The subcutaneous tissue was removed and the skin samples were cultured in 24 well plates containing KGM medium (GIBCO, Invitrogen) at 37C for 48 hours. The cell culture supernatant was collected respectively and stored in -80C for further analysis. 2.6.1.3. Concentrations of IL-8 and other pro-inflammatory cytokines in supernatant were determined by quantitative ELISA kits (supplied by Anogen and R&D). 2.6.1.4. Statistical analysis: Kruskall-wallis, Mann-whiteny and Wilcoxon paired test. 2.6.2. The results: 2.6.2.1. Skin thickness varies in different type of skin tissue and affects the weight:

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Table 4.

Tissue weight of psoriasis skin and normal skin Psoriatic skin weight (40mm2 area) Patient Median Span 43.5mg 18~103mg Surrounding non-inflammatory skin weight (40mm2 area) patient Median Span 38.8mg 20.1~78.6mg Healthy skin weight (40mm2 area) normal person Median Span 34.7mg 16~76mg

2.6.2.2. Quantitative determination of cytokines expressed by psoriatic skin tissue and normal skin tissue: The cytokine concentration in the supernatant of the tissue culture was determined by quantitative ELISA. Considering that the weights of the tissue were different, cytokine levels in the supernatant were calculated by picogram per milligram of tissue (pg/mg). Table 5. Cytokine expression in the skin tissue culture supernatant
Cytokine IL-1 (pg/mg) IL-6 (pg/mg) IL-8 (pg/mg) GM-CSF (pg/mg) TNF- (pg/mg) INF- (pg/mg) MCAF (pg/mg) Median Span Median Span Median Span Median Span Median Span Median Span Median Span Psoriasis skin 4.0 0.3-15 226 147-550 570 198-2131 7.3 0.4-21 343 38-929 197 78-625 102 0.9-310 Non-inflammatory skin 0.7 0-3 63 18-287 38 0-677 2.4 0-13 87 0-401 25 0-108 16 0-99 Normal skin 0.6 0-2 51 0-135 35 0-109 1.7 0.3-6 29 0-93 3.4 0-19 1.7 0-5.7

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Above results showed that cytokine production in psoriasis skin was significantly higher than in non-inflammatory skin and normal control. In particular, the concentration of IL8 was the highest.

Table 6.

The IL-8 concentrations in skin tissue culture supernatant: IL-8 (pg/mg) Psoriasis skin tissue 1 2 3 4 5 6 7 8 9 10 11 2131 1852 1289 860 794 570 519 486 380 355 198

Non-inflammation skin tissue 284 35 677 0 12 110 82 0 38 40 0

Normal control 1 2 3 4 5 6 7 8 109 63 51 35 35 15 0 0

Statistical analysis: Psoriasis skin --- Non-inflammatory skin Psoriasis skin ---Normal control Non-inflammatory skin--- Normal control P=0.006 (Wilcoxon rank test) P=0.003(Mann-whiteny test) P=0.8(Mann-whiteny test)

2.7. The anti-IL-8 monoclonal antibody is able to penetrate into psoriasis-damaged tissue: The skin permeability is the ability of foreign substances to penetrate and diffuse through the skin. The skin barrier naturally has a low permeability, thus protects the body from particles and foreign toxins by not allowing them to penetrate through the surface. However, studies have shown that nanoparticles of 40nm in diameter and smaller can penetrate the skin, and dermatosis such as psoriasis and measles can weaken the skin barrier. A study (Table 7) by the medical school of university of California showed that the skin permeability in psoriasis plaque can reach 11 times, 5 times, and 2 times of the normal skin, as measured by Transepidermal Water Loss (TEWL).

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Table 7. Transepidermal water loss increased in psoriasis-damaged skin Lesion Skin TEWL( g//h) Erythrodermic psoriasis Active plaque psoriasis Chronic plaque psoriasis 36.42.26 P0.001 Significance Normal Skin TEWL( g//h) 3.51.0

16.10.97

P0.001

3.90.4

9.01.9

P< 0.05

4.10.5

Anti IL-8 antibody is a large molecule of 150 kilo-Dalton. Its entry into the skin is more difficult than small molecules. To assess if or not the antibody can penetrate the psoriasis plaque in sufficient amount, in vivo experiments have been conducted independently in two labs on voluntary patients.

2.7.1 Biopsy result from Beijing Union Hospital: 2.7.1.1. Case information: 10 patients were recruited for the study. There were 5 males and 5 females; the average age was 34 years old. The patients were treated with Abcream for 1-2 weeks. 5 psoriatic samples were collected from upper limb, 4 psoriatic samples from abdomen, and 1 psoriatic sample from lower limb. Sample from 1 patient not treated with Abcream was used as negative control. All samples were studied by immunohistochemical detection. 2.7.1.2. Method: To detect the mouse anti-IL-8 antibody in Paraffin specimen, ABC method and SPTM immunohistochemistry kits (supplied by LAB VISION) were used. The samples were treated with 10% formalin, fixed into paraffin. The de-waxed paraffin section was washed with water, and then incubated with biotinylated secondary antibody. After washing, Avidin-HPR was added and incubated with the specimen. The specimen was stained with DAB substrate for 5~10 min, and counter-stained with hematoxylin. The positive samples should show brown color in epidermic cell space.

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2.7.1.3. Results:

Fig1.

Scattered brown stain was observed in aceratosis horny layer (1040)

Fig 2. Brown stain was observed in aceratosis horny layer and superficial acanthocyte layer where the inflammatory cells gathered (1010)

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Fig 3.

No coloration in negative control (1010)

2.7.1.4. Discussion: In this study, whether anti- IL-8 in the cream was able to penetrate into psoriasis-damaged tissue was studied using ABC method. aceratosis layer was observed in 7 psoriasis samples. Scattered brown flake in Among them, 2 samples showed In

brown color in the superficial acanthocyte layer, indicating that anti-IL-8 antibody infiltrated the epidermis and accumulated in the stratum spinosum of the epidermis. contrast, anti-IL-8 antibody was not detectable in the deepest layer of the epidermis. These results indicated that the anti-IL-8 antibody didnt penetrate the epidermis or the amount of this antibody penetrated was under detection limit of this method. 2.7.2. Biopsy results from the First Hospital of Beijing University: 2.7.2.1 Material and method Mouse anti-human IL-8 antibody cold cream and blank control cream were supplied by YES Biotech Laboratory Inc. of Canada. was manufactured by OLYMPUS. A psoriasis patient with stable plaque lesion was selected for the experiment. was applied once to the plaque with gentle massage each day for 2 weeks. The cream The test ABC staining KIT was supplied by Huamei Microscope Biotechnology Company. Microtome was from BRIGHT Instrument Inc.

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sample was collected from Abcream treated plaque lesion at the left abdomen. the right abdomen.

The

control sample was collected from cream ingredients (Blank cream) treated plaque lesion at These 4mm diameter biopsy samples were frozen and cut with The anti-IL-8 antibody in these samples was The experimental design included blank controls (B1, B2) Countermicrotome to obtain frozen sections. detected by ABC method.

which were treated with blank cream (without IL-8 Ab), and a self coloration control that obliterated biotinylated anti-mouse IgG during the immuno-staining (A3). staining was used for specimen A2 and B2. 2.7.2.2. Result: Table 8. The immuno-staining results of the treated group and control group. Blank cream + + + + Biotinylation anti-mouse IgG + + + + + + + Counterstaining Brown coloration + + -

Abcream A1 B1 A2 B2 A3 +

Figure # Fig 4 Fig 5 Fig 6 Fig 7 Fig 8

Fig 4.

Tan coloration in epidermis without counter-staining

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Fig 5. No tan coloration in epidermis for blank cream

Fig 6.

Tan coloration in epidermis with counter-staining

Fig 7. No tan coloration in epidermis for blank cream.

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Fig. 8.

No tan coloration in epidermis without biotinylation anti-mouse IgG

The epidermis of the Abcream treated specimens (A1 & A2) was brown colored by the immuno-staining with (Fig. 7) or without (Fig. 4) counter-staining. Removal of the biotinylated anti-mouse IgG from the immuno-staining procedure resulted in noncoloration in Abcream treated specimen (A3, Fig.9). The blank controls (B1 & B2) were not colored by the immuno-staining with (Fig. 5, 6) or without counter-staining (Fig. 8). The data indicated that the staining was specific. psoriatic skin lesion. 3. Summary of phase II/ phase III clinical study: The immunohistochemical study showed that the anti-IL-8 antibody in Abcream reached the epidermal basal layer of

The Therapeutic Effect of Abcream Against Psoriasis, - a Multicenter Clinical Evaluation Authors: Lu Lin1, Xiangsheng Chen1, Jiabi Wang2, Fanqin Zeng3, Yijie Bai4, Kanghuaug Liao5, Chuanchao Pang6, Peiying Jing1 1. 2. 3. 4. 5. 6. The Institute of Dermatology of the Chinese National Institute of Medicine Beijing Union Hospital The Sun-Yat-Sen Memorial Hospital of Zhongshan Medical University University Hospital of Bethune Medical University Huashan Hospital of Shanghai Medical University Peoples Hospital of Liaoning Province

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3.1. Introduction Psoriasis is a chronic skin disease of unknown etiology. Multiple cytokines and inflammatory Abcream, which contains an anti-

factors may play a role in the pathogenesis of this disease. the treatment of this disease. October 1999 to June 2000. 3.2. Methodology:

IL-8 monoclonal antibody, is a topical cream developed by Yes Biotech Laboratories Ltd. for We studied the therapeutic effect of this cream on psoriasis from

Participants: The recruits were from the Institute of Dermatology of the Chinese National Institute of Medicine, Beijing Union Hospital, the Sun-Yat-Sen Memorial Hospital of Zhongshan Medical University, University Hospital of Bethune medical University, Peoples Hospital of Liaoning Province, Huashan Hospital of Shanghai Medical University. majority of the patients were in progressive phase and some were in quiescent phase. patients possess typical psoriasis symptoms. Method of the trial: It was randomized, double blinded, placebo controlled clinical trial. An The All the

open-labeled group was also included in the study. In this research, Abcream was applied to the treatment group while the control group used all other cream ingredients (Blank cream) but without the anti-IL8 antibody. Method of drug application: The cream was applied to the lesion area twice each day with The application lasted for 6 weeks.

gentle massage for several minutes. Observation:

Visit began one week prior to the treatment and continued during the treatment. The diameter of of the lesion, erythoderma, the The symptoms were scored from 0 to 4

The frequency was one visit per week. accordingly.

thickness, and other symptoms were recorded. absorption were also observed and recorded. 3.3. Result:

Adverse reactions such as irritation, allergic reaction and systemic mal-

The participants that met the design requirement were divided into treatment group (208 cases), control group (234 cases) and open-labeled group (231 cases). The recruits that actually completed the procedure were: 202 participants in the treatment group, 221 in the control group,
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and 210 in the open-labeled group.

The reason for dropping-out included missing visits, No

ineffectiveness, non-complying, local adverse effect and change of treatment protocol. group (X2=3.37, P>0.05).

significant difference in dropping out rate was observed between treatment group and control

The treatment group and control group were similar in age distribution, disease progression, plaque type and clinical phase. control group were comparable. Table 12 showed that the symptoms of the treatment group and After one week of treatment, the scores for each symptom After 3-6 weeks,

changed faster in the treatment group than in the control group (Table 13). with the control group (p<0.01 or P<0.001).

the decrease in the severity of each symptoms in the treatment group was significant comparing

The recovery rate in the treatment group was significantly higher than in the control group after 5-6 weeks of treatment (Table 14). The efficacy (Table 15) in the treatment group was higher In the openthan the control group from the first week and become more significant gradually. labeled group, the efficacy is similar to the treatment group. After 6 weeks, no significant difference (X2=2.39, P>0.05) was observed in treatment efficacy between the progressive cases and quiescent cases, in the treatment group and in the openlabeled group, indicating that Abcream had similar effects to psoriasis in the progressive phase and in quiescent phase. Comparing the treatment effect of Abcream among psoriasis of different plaque shapes, the differences in recovery rate and efficacy were statistically insignificant, indicating that Abcream had similar therapeutic effect to psoriasis of different plaque shapes. The adverse reactions in the treatment group included 7 cases of irritant erythroderma, 3 cases of pain, 1 case of itching, and 1 case of edema. was 6.5%. The rate of was 5.9%. In the control group The rate there were 7 cases of irritant erythroderma, 1 case of of necrosis, 3 cases of edema. The results indicated that the drug is safe when applied locally.

In the treatment group and open-labeled group (n=197+207), there were 9 cases of minor abnormality in lab tests after treatment: 1 in platelet counting, 1 azotemia, 2 proteinuria, and 5 in urinoscopic leukocyte counting. urinoscopic leukocyte counting. There were 8 cases of abnormality in the control group(n=215): 1 in leukocyte counting, 1 in platelet counting, 1 azotemia, 1 proteinuria and 3 in Comparing the treatment group with control group, the
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difference was insignificant. treatment.

Other factors might cause the variation during the 6 week

Table 9.

Comparison of the average psoriasis symptom scores in the treatment group and

control group prior to the treatment. Diameter of skin Erythroder lesion ma Treatment group Control group 2.06+1.03 2.00+1.00 2.86+0.89 2.81+0.87 Thickness Scales Itching Total score 11.5+3.06 11.5+3.13

2.32+0.81 2.41+0.84 1.86+0.91 2.35+0.87 2.47+0.79 1.38+1.01

Table 10.

Weekly score decrease in the treatment group and control group. Diameter Erythroderm Thickness Scales of skin a lesion Itching Total score decrease 1.44+1.81 0.91+1.42 3.59+2.97 2.15+2.02 5.40+3.61 3.16+2.83 6.02+3.96 3.55+3.23

Week 1

Treatment group Treatment group Treatment group Treatment group

0.02+0.22 0.24+0.52

0.27+0.52 0.52+0.72 0.11+0.34 0.42+0.62

0.37+0.68 0.21+0.67 0.91+0.93 0.51+0.85 1.25+1.01 0.71+0.96 1.32+0.99 0.76+1.01

Control group 0.02+0.15 0.14+0.38 Week 3 0.19+0.59 0.75+0.85

0.67+0.78 1.06+0.95 0.38+0.56 0.82+0.75 1.08+0.92 1.49+1.07 0.56+0.75 1.17+0.94 1.22+0.97 1.61+1.07 0.67+0.85 1.25+1.02

Control group 0.06+0.35 0.37+0.64 Week 5 0.40+0.79 1.18+1.04

Control group 0.11+0.57 0.61+0.86 Week 6 0.52+0.95 1.34+1.16

Control group 0.16+0.65 0.70+0.93

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Table 11.

Recovery rate (%) Open-labeled group Treatment group 0 1.5 5.9 15.3 Control group X2 0 0.5 0.9 2.7 6.86 21.1 P value 0.35 <0.01 <0.001

Week 1 Week 3 Week 5 Week 6

0 3.8 6.2 12.9

Table 12.

Efficacy (%) Open-labeled group Treatment group 2.5 12.9 41.1 49 Control group X2 0 3.2 12.2 14.9 4.14 45.72 57.09 P value <0.05 <0.001 <0.001 <0.001

Week 1 Week 3 Week 5 Week 6 3.4 Summary:

0.5 11.9 38.1 53.8

This phase II/III clinical trial used multicenter, randomized, double-blinded, placebo controlled method to study the therapeutic effect of Abcream on 412 regular cases of psoriasis. According to the results, the scores for the diameter of the plaque, erythroderma, thickness, scale and itching started to decrease after one week. From week 3 to week 6, the changes in After 6 weeks of treatment, The recovery rate in The effect of the 5 indicators became significant in the Abcream treated group.

the recovery rate was 15.3% in the Abcream treated group, and 2.7% in the control group. The efficacy was 49% in the treatment group and 14.9% in the control group. the open-labeled group was 12.9% and the efficacy is 53.8%. The results proved the The rate of adverse

therapeutic effect of anti-IL-8 antibody containing Abcream on psoriasis. Abcream on psoriasis of different phases and plaque types were similar. control group (n=228).

reaction is 5.9% in the treatment group (n= 202). The rate of adverse reaction is 6.6% in the

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Affected Areas Before and After Abcream Topical Treatment

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