Chapter 5 5 Efalizumab: Antibody Characteristics, Mode of Action and Preclinical Development S.Jahn,K.Schmitt-Rau

5.1 ICAM expression can be triggered by pro-inflam- Introduction matory mediators, such as tumour necrosis factor- [ (TNF- [ )andinterferon-* (IFN- * ). Efalizumab is a humanized monoclonal antibody bind- LFA-1 antagonism has the potential to differentially ing to the lymphocyte function-associated antigen affect functions of distinct T-cell populations as LFA-1 q (LFA-1).LFA-1belongstothefamilyof 2 integrins and is expressed at higher levels on memory than on na¨ıve is expressed on the surface of T cells (CD4+ cells, T- T-cell populations. Monoclonal antibodies (mAbs) to helper cells; CD8+ cells, cytotoxic T cells). LFA-1 is LFA-1 or its ligands have been found to inhibit T-cell essential for every step in the process of immune sur- activation in vitro, to inhibit T-cell-dependent T-cell veillance and mounting an immune response (Dustin responses, to inhibit lymphocyte proliferation et al. 2004): (1) firm adherence to the wall of blood ves- responses, to reduce lymphocyte trafficking and hom- sels under blood flow, (2) scanning by T cells of other ing, and to reduce adhesion of T cells to endothelial cellswithintissues,and(3)formationoftheimmuno- cellsinvitro.Therefore,itmaybeproposedthatthe logical synapse between T cells and antigen-presenting inhibition of LFA-1/ICAM interaction leads to a sup- cells (APCs). pression of several T-cell-dependent immune func- q LFA-1, Mac-1 and p159,95, members of the 2 inte- tions, which are crucial for the pathogenesis of inflam- grin family, are heterodimeric molecules consisting of matory autoimmune diseases, namely (auto)-antigen a q -subunit (CD18), common to all three molecules, presentation (Fig. 5.1a) and immune cell migration which is non-covalently linked to the respective [ - from blood flow to the target tissue (Fig. 5.1b). Results chain CD11a (LFA-1), CD11b (Mac-1), and CD11c derived from animal models imply that inhibiting LFA- (p159,95). T cells mainly express LFA-1 (CD11a/CD18). 1/ICAM interaction by anti-CD11a antibodies may LFA-1 expression is regulated by activation of T cells have a clinical benefit in certain T-cell-dependent dis- which may induce a conformation change in the mole- eases. CD11a blockade is predicted to produce less cule resulting in a switch of the LFA-1 affinity from a global immune suppression compared with CD18 low- to a high-affinity state as the T cell moves on from blockade because T cells are relatively dependent on a resting to an activated state. The LFA-1 affinity matu- CD11a/CD18 (LFA-1) in contrast to other types of leu- ration is influenced by a whole complex of so called cocytes. “inside-out” signals, like activation of specific G-pro- A humanized monoclonal anti-CD11a IgG1 anti- tein-coupled receptors, cytokine stimulation of motili- body, efalizumab, therefore showed clinical efficacy in ty, and T-cell-receptor-mediated signals following anti- psoriasis and other T-cell-mediated autoimmune dis- gen binding by the respective T-cell receptor (TCR). eases and is actually registered for the indication The ligands for LFA-1 are intercellular adhesion plaque psoriasis. molecules (ICAMs). They include ICAM-1, expressed on leucocytes, vascular endothelium cells and epitheli- al cells, including keratinocytes, ICAM-2 expressed on resting endothelium and lymphocytes and ICAM-3, expressed on monocytes and resting lymphocytes. 5.2 Development and Characterization of the Antibody 43

a

b

Fig. 5.2. Humanized monoclonal antibody efalizumab. CDR complementarity determining regions, FR framework regions, VH variable part of the heavy chain, VL variable part of the light chain

IgG1. The molecular weight of intact efalizumab is 148,841 daltons. Originally developed as a murine anti-CD11a mono- clonal antibody (MHM24; Hildreth and August 1985), efalizumab has been prepared by substituting human DNA sequences using genetic engineering methods to reduce immunogenicity. In detail, complementarity determining regions (CDRs) from the murine antibody Fig. 5.1. a Scheme of antigen presentation by an antigen-pre- MHM24 were grafted into consensus human IgG1 V senting cell (APC)toTcells.Open circle indicates the partici- heavy and light chain sequences. This results in a pationofLFA-1/ICAM-1interactionintheformationofthe “humanized” mAb (HuIgG1) in which the CDRs of the immunological synapse. b Scheme of adhesion molecule inter- action between leucocytes and endothelial cells. Asterisk indi- murine antibody – important for specific antigen rec- cates LFA-1/ICAM-1 interaction ognition – are preserved. Previous studies on murine MHM24 have shown that, similar to other anti-CD11a antibodies, it is able to 5.2 inhibit T-cell function. Development and Characterization The consensus sequences for the human heavy chain of the Antibody subgroup III (VH-CH1)andthelightchainsubgroupk 1 were used as the framework for the humanization Efalizumab (rhuMAb CD11a, hu1124) is a full-length, (Fig. 5.2). Several humanized variants were made and IgG1 kappa isotype antibody composed of two identi- screened for binding as Fabs. To construct the first Fab cal kappa light chains consisting of 214 amino acid resi- variant of humanized MHM24, all six CDR residues dues,andtwogammaheavychainsconsistingof451 were transferred from the murine antibody to the residues. Each light chain is covalently coupled through human framework. a disulphide link to a heavy chain. The two heavy chains Further variants were constructed by targeted are covalently coupled to each other via inter-chain dis- exchange of either framework residues, or residues ulphide bonds consistent with the structure of human within CDRs using the first variant (Fab-1), as a tem- 44 5 Efalizumab: Antibody Characteristics, Mode of Action and Preclinical Development

plate. For that purpose, both light and heavy chains anywhere on the body. Other, less frequent, morpholo- were completely sequenced for each variant. Plasmids gies of psoriasis include guttate, inverse, pustular, and containing the sequences were then transformed to erythrodermic forms. They may occur individually, Escherichia coli for protein expression. concomitantly or sequentially. All variants were tested for CD11a binding in the There is agreement today that immunological mech- Jurkat cell assay. VL and VH domains of the variant with anisms play an important role in the pathogenesis of optimal binding characteristics were then transferred many chronic relapsing inflammatory skin diseases, to human IgG1 constant domains, giving the full- such as psoriasis (Krueger 2002; Schoen and Boehncke length intact humanized antibody (Werther et al. 2005). Evidence of the pivotal role played by T cells in 1996). the pathology of psoriasis is accumulating. Several in vitro assays were performed to compare ) Activated T cells are found in psoriatic lesions. efalizumab with its parent murine antibody MHM24, ) T cells have the ability to induce the altered kerati- including the keratinocyte cell-adhesion assay and the nocyte growth and differentiation pattern typical mixed lymphocyte response assay (MLR). of psoriasis. This has been demonstrated in a SCID The results showed that, in these assays, efalizumab mouse model by injecting autologous immunocy- worked as well as MHM24. In addition, the apparent K d tes into the dermis of mice that have received grafts values, as determined by saturation binding using of human skin. Plaques typical of those seen in peripheral blood mononuclear cells (PBMCs) of two psoriasis are observed when immunocytes from a human donors, were similar for both MHM24 and efa- patient with psoriasis are injected into a mouse lizumab (0.16±0.01 nM and 0.13±0.02 nM vs possessing a graft of symptom-free skin from the 0.11±0.08 nM and 0.18±0.03 nM, respectively). same patient. ) T-cell-targeted immune suppressive drugs, such as 5.3 cyclosporine, and antibodies against the CD25 receptor and CD4, have been shown to improve Efalizumab: From Mode of Action psoriasis. to the Treatment of Psoriasis ) In bone marrow transplantation, psoriasis can be 5.3.1 transferred from a donor suffering from the dis- Psoriasis: Prevalence, Characteristics and Therapeutic ease to a healthy recipient. Also, psoriasis can be Options “cured” when bone marrow is transplanted from a healthy donor to a person with psoriasis. Psoriasis is one of the most common dermatological ) When symptomless skin from psoriasis patients diseases. Although there is a great variation in the prev- was engrafted onto AGR129 mice, deficient in type alence of psoriasis in different countries due to envi- I and type II interferon receptors and for the ronmental and genetic factors, it can be said that it recombination activating gene 2, resident human affects roughly 2–3% of the world’s Caucasian popula- T cells in the skin grafts underwent local prolifera- tion.About20–25%ofthesepeoplesufferfrommod- tion, demonstrating the importance of resident erate-to-severe forms of the disease. immune cells in the development of psoriasis. Themajorityofpatientswithplaquepsoriasis (75%) show first signs of disease manifestation before There is a whole battery of treatment options available the age of 40 years, with a peak in the second decade of today. The mild forms of psoriasis are usually treated life. These patients usually have a family history of pso- with topical preparations, including vitamin D3 analo- riasis, their disease is more severe, and it is character- gues, corticosteroids and retinoids. When the disease ized by frequent relapses. The most common form of becomes severe, phototherapeutic regimens are psoriasis, with a prevalence of about 70%, is plaque applied. Finally, there is the option to use an oral psoriasis or “psoriasis vulgaris”. Plaque psoriasis is immune suppressive drug, such as methotrexate, cyclo- characterized by hyperkeratosis, parakeratosis and the sporin, oral retinoids, or fumaric acid esters, as mono- presence of inflammatory lesions in the skin. There is a therapy or in combination. As the majority of patients predilection for symmetrical involvement of the scalp, develop their disease before the age of 40 years, many of elbows, knees and lower back. It can occur, however, those with moderate-to-severe psoriasis will require 5.3 Efalizumab: From Mode of Action to the Treatment of Psoriasis 45

Fig. 5.3. Scheme of the immune pathogenesis of psoriasis and the proposed mechanisms of LFA-1 blockade by the CD11a anti- body efalizumab. Points of action for efalizumab are indicated decades of continuous systemic or phototherapy. sed subjects, keratinocyte-derived peptides may be Unfortunately, none of the available therapies can be involved. used chronically, because of long-term safety and toxic- The APC–antigen complex migrates to a skin-drain- ity problems. ing lymph node, where the antigen is presented via Recent advances in the understanding of T-cell inter- major histocompatibility complex II (MHC II) on the actions in the pathogenesis of psoriasis have led to the surface of the APC to the T-cell receptor (TCR) of the development of several biological substances, such as the specific na¨ıve CD4+ cell, or via MHCI to the TCR of targeted T-cell modulator efalizumab, for continuous CD8+ T cells respectively. Interaction of the APC-MHC- immune therapy of this disease, without the safety prob- II/antigen–TCR complex is, however, not sufficient for lems of the traditional systemic preparations (Fig. 5.3). T-cell activation. The initial binding of T cells and APCs, as well as sta- bilization of the cell pair, is mediated by LFA-1 on T cell 5.3.2 and ICAM-1 on the APC. This stabilized structure has Pathogenesis of Psoriasis: Targets for Efalizumab been referred to as the “immunological synapse” 5.3.2.1 (Fig.5.1a),formationofwhichisfollowedbydelivery T-Cell Activation of the antigen-specific signal (signal 1) and a costimu- The first step in the immune pathogenic cascade of pso- latory signal (signal 2), which are also mediated by riasis is the capture and processing of auto-antigen by LFA-1 and ICAM-1. Delivery of signal 1 and signal 2 is Langerhans cells or dendritic cells (”antigen-present- followed by binding of cytokines that induce T cells to ing cells” [APCs]) in the epidermis or dermis, respec- proliferate (i.e. undergo clonal expansion) and differ- tively. The nature of the antigen is still unknown. There entiate. Proliferation is thought to be largely mediated is, however, some evidence that in genetically predispo- bythecytokineinterleukin-2(IL-2). 46 5 Efalizumab: Antibody Characteristics, Mode of Action and Preclinical Development

phocyte/keratinocyte interactions could be involved, 5.3.2.2 or cytokines produced during T-cell re-activation may T-Cell Migration and Extravasation be responsible for the most prominent alteration in Followingactivation,Tcellsleavethelymphnodeand psoriatic skin: hyperproliferation. start trafficking via the bloodstream to the dermal ves- In summary, a combination of different mechanisms sels(Fig.5.1b).Stimulationbykeratinocyte-derived may be responsible for the changes observed histologi- cytokines (IL-8, CCL27) leads to increased expression cally and clinically in psoriatic skin. These include: of adhesion molecules, including E-selectin and ICAM- ) Increased proliferation of keratinocytes (hyperker- 1, in the post-capillary venules of inflamed skin. E- atosis) selectin is the target for cutaneous lymphocyte antigen ) Neutrophil and mast-cell migration into epidermis (CLA) on the T-cell surface. Binding of CLA to E-selec- and dermis, respectively tin, as well as the interaction of the lymphocyte chemo- ) Increased production of defensins by activated kine receptor (CCR10) with its ligand CCL27, slows cir- keratinocytes culating lymphocytes and causes their “rolling” along ) Increased angiogenesis the endothelial wall. As a result of increased exposure to chemokines, the affinity of LFA-1 for ICAM-1 is increased, probably 5.3.3 mediated by a conformational change in the LFA-1 Efalizumab: Mechanism of Action molecule. Bound T cells flatten and pass through the epithelium into the surrounding tissue – a process As already described, efalizumab is a humanized known as diapedesis. Once they have left the venule, T monoclonal antibody against CD11a, the [ -subunit of cells respond to chemokines; drawing them towards LFA-1. Binding of efalizumab to CD11a leads to block- the site of inflammation in the dermis, and from there ade of the interaction between LFA-1 and ICAM-1. The into the epidermis. blockade of this interaction has several consequences (Jullien et al. 2004) (Fig. 5.1), including activation of T lymphocytes in lymph nodes 5.3.2.3 T-Cell Reactivation ) Inhibition of extravasation of circulating lympho- cytes in inflammatory skin Following transmigration from the circulation into der- ) BlockadeofT-lymphocytere-activationinskinby mal and epidermal tissue, memory T cells are brought APCs into contact with antigen-presenting dendritic and Lan- ) Reduction of the keratinocyte interaction with gerhanscells,aswellaswithkeratinocytes,which,proba- activated T lymphocytes bly due to genetic alterations, are also able to act as APCs. This interaction leads to the re-activation of T cells and is Therapeutic administration of efalizumab induces an followed by increased production and secretion of cyto- increase of both na¨ıve and memory populations of kines, including IL-2, IFN- * and TNF- [ ,whichshowthe CD4+ and CD8+ lymphocytes in peripheral blood. The TH-1 cytokine pattern typically observed in psoriasis. largest increase was detected for memory CD8+ cells. This CD8+ memory T-cell subpopulation represents ) IFN- * leads to induction of ICAM-1 in keratinocy- the most prominent T-cell subset found in psoriatic tes and endothelium, and consequently supports skin lesions. Furthermore, an increase in Type I (IFN * - binding of lymphocytes to keratinocytes. producing) T cells during treatment was described. ) TNF- [ induces keratinocyte proliferation and Results of histological analysis of lesional tissue indi- stimulates keratinocyte-induced interleukin-8 cated a significant decrease of memory T-cell counts in (IL-8) production. This leads to chemotaxis of the epidermis and dermis, correlating with a decrease lymphocytes and neutrophils into the epidermis. in mean epidermal thickness in the majority of efalizu- TNF- [ is also able to induce activation and prolif- mab-treated patients. It can be concluded therefore eration of endothelial cells. that highly pathogenesis-relevant T-cell subsets are However, the exact mechanism by which (re-)activated blockedfromcutaneousentrybyefalizumab.Byinter- Tcellscausepsoriaticlesionsisnotknown.Directlym- acting with the CD11a subunit of LFA-1, efalizumab 5.4 Pharmacology and Toxicology of Efalizumab 47 inhibits the formation of the immunological synapse of 5.4.2 T cells, once in the skin, with APCs and therefore their Pharmacodynamics antigen-specific activation. By inhibiting these processes, efalizumab may be The pharmacodynamic properties of efalizumab were abletopreventabnormalcytokineproduction,kerati- investigated in several Phase I and Phase II studies fol- nocyte hyperproliferation and abnormal keratinocyte lowing intravenous and subcutaneous administration, differentiation, which are characteristic of the psoriatic either as a single dose or repeated weekly administra- phenotype. tion. In the single-dose intravenous study, doses of 0.03–10 mg/kg were given. Within 24 h, treatment with 5.4 efalizumab reduced the level of CD11a expression on T Pharmacology and Toxicology of Efalizumab cells to 25% of pretreatment levels. This suppression persisted as long as efalizumab was present in the cir- 5.4.1 culation. In the above mentioned study (i.v., single Preclinical Studies dose), CD11a expression returned to baseline within A number of preclinical studies have been conducted 7–10 days following clearance of efalizumab, without with efalizumab to evaluate its pharmacodynamic and showing any signs of lymphocyte depletion. Total white pharmacokinetic properties, as well as its toxicity. blood cell (WBC) count was slightly increased within In vitro studies performed with efalizumab have about 8 h of efalizumab administration; circulating shown that it is able to bind to human and chimpanzee lymphocyte counts were increased by day 7. Following leucocytes, inhibit lymphocyte binding to ICAM-1 on multiple weekly dosing, lymphocytes remained elevat- keratinocytes and inhibit T-cell proliferation. In ed but returned to baseline after efalizumab clearance. murine and chimpanzee in vivo models, efalizumab This elevation of lymphocyte count is probably due to wasabletodown-regulateLFA-1expressiononlym- demargination – blocked entry of efalizumab-bound phocytes, while efalizumab has been shown to have cells to tissues. two-compartment kinetics with non-linear elimination To achieve the full pharmacodynamic effect, intra- in monkeys. venous doses of above 0.3 mg/kg were necessary. Com- Anti-mouse CD11a antibodies have been used to plete saturation and maintenance of CD11a binding study developmental toxicity in mice. In these studies, site down-regulation on lymphocytes required weekly doses were administered at up to 30 times the equiva- intravenous doses of 0.6 mg/kg, which corresponds to lent recommended clinical dose of 1 mg/kg. No adverse an efalizumab plasma concentration of 5 μg/ml. effects were observed on mating, fertility or reproduc- Several histological changes were observed in psori- tiveparameters.Therewasalsonoevidenceofmater- atic plaques following efalizumab administration. A nal toxicity, embryotoxicity or teratogenicity. marked reduction of keratin-16, corresponding to Similarly to other immunoglobulins, anti-mouse decreased disease activity, was noted. Keratinocyte CD11a antibody is secreted in the milk of lactating mice ICAM-1 levels were also reduced, indicating reduced thatareexposedtotheantibodyduringgestationand cytokine-mediated inflammation. Furthermore, a sig- lactation. Furthermore, a significant reduction was nificant thinning of the epidermis and restoration of observed in the ability of their offspring to generate an normal skin was observed after 28 days of treatment, in antibody response at 11 weeks of age, which was – at concordance with reductions of over 50% in cutaneous least partially – reversible at week 25. There were, how- T-cell infiltration and reduced CD11a availability. ever, no adverse effects on behaviour, growth and These data demonstrate that by reducing CD11a on the reproductive function of the offspring. surface of circulating and cutaneous T cells, efalizumab Immunization of chimpanzees exposed to high doses is able to reverse both the histological signs of inflam- of efalizumab (>10 times the clinical dose) with tetanus mation and the pathological hyperplasia characteristic toxoid produced an impaired antibody response com- of plaque psoriasis. pared with control animals. However, there have been In general, the effects of subcutaneous efalizumab no animal reproduction studies and long-term carcino- on lymphocytes were comparable to those observed genicity studies conducted with efalizumab. after intravenous dosing. Subcutaneous doses of 48 5 Efalizumab: Antibody Characteristics, Mode of Action and Preclinical Development

1 mg/kg/week or above produced the required efalizu- 5.4.3.3 mab plasma concentrations of 5 μg/ml for binding site Biotransformation down-regulation and saturation. No additional clinical benefits of higher doses (e.g. doses of 2 mg/kg/week The metabolism of efalizumab is through internaliza- and 4 mg/kg/week) were observed. tion followed by intracellular degradation as a conse- In addition to reduced CD11a expression on the sur- quence of either binding to cell surface CD11a or face of CD3+ T cells, binding of efalizumab also causes through endocytosis. The expected degradation prod- a reduced expression of other adhesion molecules, such ucts are small peptides and individual amino acids q as CD11b, L-selectin or 7 integrin. The down-modula- which are eliminated by glomerular filtration. Cyto- tion of these adhesion molecules likely contributes to chrome P450 enzymes, as well as conjugation reac- the anti-adhesive effects of efalizumab. There is also a tions, are not involved in the metabolism of efalizumab. decrease of [ q + T-cell receptors and of TCR-associated co-receptors, such as CD4, CD8 or CD2. Inhibition of 5.4.3.4 TCR-mediated activation therefore seems to also play a Elimination role in efalizumab’s mode of action. Efalizumab is cleared by dose-dependent non-linear saturable elimination. Mean steady-state clearance is 5.4.3 24.3±18.5 and 15.7±12.6 ml/kg/day for the 1 mg/kg/ Pharmacokinetics week and 2 mg/kg/week groups, respectively. The elim- The pharmacokinetic properties of subcutaneous efali- inationhalf-lifewasabout6.21±3.11daysforthe1mg/ zumab were determined in an open, multicentre, Phase kg/week group and 7.4±2.5 days in the 2 mg/kg/week I study of 70 patients suffering from moderate-to- group. Tend at steady state is 25.5±1.6 days at 1 mg/kg/ severe plaque psoriasis. Patients received weekly doses week and 44±10 days at 2 mg/kg/week. of either 1 mg/kg (n=33) or 2 mg/kg (n=37) efalizu- Efalizumab shows dose-dependent non-linear phar- mab for 12 weeks subcutaneously. macokinetics, which can be explained by its saturable specific binding to cell surface receptors CD11a. Clear- ance was more rapid at lower doses, suggesting a recep- 5.4.3.1 tor-mediated mechanism at drug levels below 10 μg/ml. Absorption In a population pharmacokinetic analysis of 1,088 After subcutaneous administration of efalizumab, peak patients, body weight was found to be the most signifi- plasma concentrations are reached after 2–3 days. The cant covariate affecting efalizumab clearance. Other average estimated bioavailability was about 50% at the covariates such as baseline Psoriasis Area and Severity recommended dose level of subcutaneous efalizumab, Index (PASI), baseline lymphocyte count and age had 1.0 mg/kg/week. modest effects on clearance; gender and ethnic origin had no effect. Additional pharmacokinetic data are available from 5.4.3.2 an open-label extended treatment trial in which Distribution patients who responded to an initial treatment of efali- Steady-state serum concentrations of efalizumab were zumab, 2 mg/kg, for 12 weeks, received the drug in a achieved after four doses of weekly efalizumab, 1 mg/ maintenance phase for up to 33 months at a dose of kg,andafter8weeksinpatientsreceiving2mg/kg.At 1 mg/kg. Pharmacokinetic analysis of each 12-week this dose level (with an initial dose of 0.7 mg/kg in the treatment period for up to 15 months showed that first week), the mean efalizumab plasma trough values steady-state trough levels remained constant during were 9.1±6.7 μg/ml in the 1 mg/kg group and continuous efalizumab dosing. There was no evidence 23.5±12.2 μg/ml in the 2 mg/kg group. Volumes of dis- of efalizumab accumulation or alteration of the phar- tribution of the central compartment after single intra- macokinetic profile of efalizumab during long-term venous doses were 110 ml/kg at dose 0.03 mg/kg and continuous dosing. 58 ml/kg at dose 10 mg/kg. References 49

5.5 sion during cellular interactions that are important for Indication(s) induction and maintenance of immune-mediated inflammatory processes. Efalizumab (Raptiva) is indi- The European Medicines Agency (EMEA) approved cated for treatment of adult patients with moderate to efalizumab (Raptiva) for the treatment of adult patients severe chronic plaque psoriasis who have failed to with moderate to severe chronic plaque psoriasis who respond to, or who have a contraindication to, or are have failed to respond to, or who have a contraindica- intolerant to, other systemic therapies including cyclo- tion to, or are intolerant to, other systemic therapies sporine, methotrexate and PUVA. including cyclosporine, methotrexate and PUVA. The Food and Drug Administration (FDA) approved efalizumab for the treatment of adult patients References ( & 18 years old) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or Dustin ML, Bivona TG, Philips MR (2004) Membranes as mes- phototherapy. sengersinTcelladhesionsignaling.NatureImmunol5: 363–372 Efalizumab was tested in a phase II study to treat Hildreth JEK, August JT (1985) The human lymphocyte func- psoriasis arthritis. However, there was no significant tion-associated (HLFA) antigen and a related macrophage clinical improvement detected in treated patients in differentiation antigen (HMac-1): functional effects of sub- comparison with the placebo group. unit-specific monoclonal antibodies. J Immunol 134:3272– Case reports were published about the use of efalizu- 3280 JullienD,PrinzJC,LangleyRGB,CaroI,DummerW,JoshiA, mab in patients with dermatomyositis, palmo-plantar Dedrick R, Natta P (2004) T-cell modulation for the treat- pustulosis or atopic dermatitis. ment of chronic plaque psoriasis with efalizumab (Rapti- va™): mechanisms of action. Dermatology 208:297–306 Krueger JG (2002) The immunologic basis for the treatment of 5.6 psoriasis with new biologic agents. J Am Acad Dermatol 46: 1–23 Summary Schön MP, Boehncke W-H (2005) Medical progress: psoriasis. N Engl J Med 352:1899–1912 Efalizumab is a humanized monoclonal antibody bind- Werther WA, Gonzalez TN, O’Connor SJ, McCabe S, Chan B, ing to lymphocyte function-associated antigen (LFA-1). Hotaling T, Champe M, Fox JA, Jardieu PM, Berman PW, q Prestal LC (1996) Humanization of an anti-lymphocyte LFA-1belongstothefamilyofthe 2 integrins and is function-associated antigen (LFA)-1 monoclonal antibody expressed on the surface of T cells (CD4+ cells, T-help- and reengineering of the humanized antibody for binding to er cells). It is involved in several T-cell activities, such as rhesus LFA-1. J Immunol 157:4986–4995 T-cell activation and migration, as well as T-cell adhe-