Maturation of periodontal tissues following implantation of rhGDF-5/ß-TCP in one-wall intra-bony defects in dogs: 24-week histological observations.

OBJECTIVE: Although a previous study reported that recombinant human growth/differentiation factor-5 (rhGDF-5) coated onto a ß-tricalciumphosphate (ß-TCP) significantly enhanced periodontal regeneration, the long-term stability/maturation of the regenerated tissues has not been demonstrated. The objective of this study was to evaluate periodontal regeneration/maturation following application of rhGDF-5/ß-TCP using an established periodontal defect model and a 24-week healing interval. MATERIAL & METHODS: Unilateral, surgically created, 4 × 4 × 5 mm (length × width × height), one-wall, critical-size, intra-bony periodontal defects at the mandibular second and fourth premolar teeth in five young adult Beagle dogs received rhGDF-5/ß-TCP. Bilateral sites at the fourth premolar in the other four dogs served as pristine controls receiving mucogingival flap surgery without defect induction. The animals were euthanized at 24 weeks for histological analysis. Unpublished data from the previous 8-week study were used to compare tissue maturation between 8 and 24 weeks. RESULTS: Linear histometric observations of cementum and alveolar regeneration showed no significant differences between the 8- and 24-week observation intervals. However, parameters of periodontal tissue maturation showed significant differences between the observation intervals including increased fraction mineralized tissue and lamellar bone (p < 0.05) and decreased osteocyte counts (p < 0.05) at 24 weeks compared with 8 weeks. Although the count inserting Sharpey's fibre did not significantly change, regenerated cementum remote from the intact periodontal ligament appeared more highly mineralized and thicker at 24 weeks compared with 8 weeks, and compared with the pristine cementum. Minimal ß-TCP remained. CONCLUSIONS: These 24-week observations suggest that regenerated periodontal tissues in sites receiving rhGDF-5/ß-TCP undergo progressive maturation without debilitating aberrant tissue reactions.

Maturation of alveolar bone following implantation of an rhGDF-5/PLGA composite into 1-wall intra-bony defects in dogs: 24-week histometric observations.

OBJECTIVE: The aim of this study was to evaluate long-term (24 weeks) alveolar bone maturation following surgical application of recombinant human growth/differentiation factor-5 (rhGDF-5) in an injectable poly-lactide-co-glycolide-acid (PLGA) composite carrier using an established periodontal defect model. METHODS: Routine, bilateral, 4 × 5 mm (width × depth), 1-wall, critical-size, intra-bony periodontal defects were surgically created at the 2nd and 4th mandibular premolar teeth in 10 Beagle dogs. The animals were randomized to receive (split-mouth design; defect sites in the same jaw quadrant getting the same treatment) rhGDF-5/PLGA high dose (188 µg/defect) versus sham-surgery control (5 animals), and rhGDF-5/PLGA low dose (37 µg/defect) versus carrier control (5 animals). The animals were euthanized for histometric analysis following a 24-week healing interval. RESULTS: Clinical healing was uneventful. The rhGDF-5 high dose significantly increased bone formation compared with controls in terms of bone area (p < 0.05), and a high degree of bone maturation was observed in the rhGDF-5/PLGA high dose group. Root resorption/ankylosis or other aberrant healing events were not observed. CONCLUSION: The rhGDF-5/PLGA appears to support alveolar bone healing/regeneration and the rhGDF-5/PLGA high dose uniquely increased maturation of the regenerated bone.

Wound healing/regeneration using recombinant human growth/differentiation factor-5 in an injectable poly-lactide-co-glycolide-acid composite carrier and a one-wall intra-bony defect model in dogs.

OBJECTIVE: The purpose of this study was to evaluate the effect of recombinant human growth/differentiation factor-5 (rhGDF-5) on periodontal wound healing/regeneration using an injectable poly-lactide-co-glycolide-acid (PLGA) composite carrier and an established defect model. METHODS: Bilateral 4 × 5 mm (width × depth) one-wall, critical-size, intra-bony periodontal defects were surgically created at the second and the fourth mandibular pre-molar teeth in 15 Beagle dogs. The animals were randomized to receive (using a split-mouth design; defect sites in the same jaw quadrant getting the same treatment) rhGDF-5 high dose (188 µg/defect) versus sham-surgery control (five animals), rhGDF-5 mid dose (37 µg/defect) versus carrier control (five animals), and rhGDF-5 low dose (1.8 µg/defect) versus treatment reported elsewhere (five animals). The animals were euthanized for histometric analysis following an 8-week healing interval. RESULTS: Clinical healing was uneventful. The rhGDF-5/PLGA construct was easy to assemble and apply. The rhGDF-5 high dose supported significantly increased bone formation compared with the low-dose, sham-surgery, and carrier controls (p<0.05) and induced significantly increased cementum formation compared with the controls (p<0.05). Root resorption/ankylosis or other aberrant healing events were not observed. CONCLUSION: rhGDF-5 appears to effectively support periodontal wound healing/regeneration in a dose-dependent order; the PLGA composite appears to be an effective ease-of-use candidate for carrier technology.

Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein.

SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.

Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 in a beta-tricalcium phosphate carrier into one-wall intrabony defects in dogs.

OBJECTIVE: Recombinant human growth/differentiation factor-5 (rhGDF-5) is being evaluated as a candidate therapy in support of periodontal regeneration. The objective of this study was to evaluate periodontal wound healing/regeneration following the application of rhGDF-5 on a particulate beta-tricalcium phosphate (beta-TCP) carrier using an established defect model. MATERIALS AND METHODS: Bilateral 4 x 5 mm (width x depth), one-wall, critical-size, intrabony periodontal defects were surgically created at the mandibular second and fourth pre-molar teeth in 15 Beagle dogs. Unilateral defects in five animals received rhGDF-5/beta-TCP (Scil Technology GmbH); five animals received beta-TCP solo; and five animals served as sham-surgery controls. Contralateral sites received treatments reported elsewhere. The animals were sacrificed following an 8-week healing interval for histological examination. RESULTS: Clinical healing was generally uneventful. Sites implanted with rhGDF-5/beta-TCP exhibited greater enhanced cementum and bone formation compared with beta-TCP and sham-surgery controls; cementum regeneration averaged (+/- SD) 3.83 +/- 0.73 versus 1.65 +/- 0.82 and 2.48 +/- 1.28 mm for the controls (p<0.05). Corresponding values for bone regeneration height averaged 3.26 +/- 0.30 versus 1.70 +/- 0.66 and 1.68 +/- 0.49 mm (p<0.05), and bone area 10.45 +/- 2.26 versus 6.31 +/- 2.41 and 3.00 +/- 1.97 mm(2) (p<0.05). Cementum regeneration included cellular/acellular cementum with or without a functionally oriented periodontal ligament. A non-specific connective tissue attachment was evident in the sham-surgery control. Controls exhibited mostly woven bone with primary osteons, whereas rhGDF-5/beta-TCP sites showed a noticeable extent of lamellar bone. Sites receiving rhGDF-5/beta-TCP or beta-TCP showed some residual beta-TCP granules apparently undergoing biodegradation without obvious differences between the sites. Sites receiving beta-TCP alone commonly showed residual beta-TCP granules sequestered in the connective tissue or fibrovascular marrow. CONCLUSION: rhGDF-5/beta-TCP has a greater potential to support the regeneration of the periodontal attachment. Long-term studies are necessary to confirm the uneventful maturation of the regenerated tissues.

Evaluation of an injectable rhGDF-5/PLGA construct for minimally invasive periodontal regenerative procedures: a histological study in the dog.

AIM: To evaluate the injectability, biocompatibility, safety, and periodontal wound healing/regeneration following application of a novel bioresorbable recombinant human growth/differentiation factor-5 (rhGDF-5)/poly(lactic-co-glycolic acid) (PLGA) construct. MATERIAL AND METHODS: Periodontal pockets (3 x 6 mm, width x depth) were surgically created over the buccal roots of the second and fourth mandibular pre-molars in eight adult Hound Labrador mongrel dogs. Surgeries including injection of the rhGDF-5/PLGA construct into the pockets were sequenced that four animals provided 2-/4-week and four animals 6-/8-week observations of sites receiving rhGDF-5/PLGA or serving as sham-surgery control. RESULTS: The rhGDF-5/PLGA construct was easy to prepare and apply. Approximately 0.2 ml (93 microg rhGDF-5)/tooth was used. Clinical and radiographic healing was exemplary without adverse events. Healing was characterized by a non-specific connective tissue attachment, acellular/cellular cementum, periodontal ligament (PDL), bone regeneration, and a junctional epithelium. PLGA fragments were observed in 4/7, 2/8, and 1/8 sites at 2, 4, and 6 weeks, respectively. Associated inflammatory reactions exhibited no limiting effect on periodontal wound healing/regeneration. Root resorption/ankylosis was not observed. Bone formation showed apparent increased maturity (lamellar bone) at 6 weeks in sites receiving rhGDF-5/PLGA compared with the control. Both protocols exhibited significant increases in PDL, cementum, and bone regeneration over time, without significant differences between treatments. In time, PDL and cementum regeneration was twofold greater for the control at 4 weeks (p=0.04) while increased bone formation was observed at sites receiving rhGDF-5/PLGA (p<0.01). CONCLUSIONS: In conclusion, the rhGDF-5/PLGA construct appears to be a safe technology for injectable, ease-of-use application of rhGDF-5-stimulated periodontal wound healing/regeneration. Additional work to optimize the polymer carrier and rhGDF-5 release kinetics/dose might be required before evaluating the efficacy of this technology in clinical settings using minimally invasive approaches.

Growth/differentiation factor-5 significantly enhances periodontal wound healing/regeneration compared with platelet-derived growth factor-BB in dogs.

OBJECTIVE: Recombinant human growth/differentiation factor-5 (rhGDF-5) in a particulate beta-tricalcium phosphate (beta-TCP) carrier is being evaluated to support periodontal regeneration. The objective of this study was to evaluate periodontal wound healing/regeneration following an established clinical (benchmark) protocol including surgical implantation of rhGDF-5/beta-TCP in comparison with that following implantation of recombinant human platelet-derived growth factor-BB (rhPDGF) combined with a particulate beta-TCP biomaterial using an established canine defect model. MATERIALS AND METHODS: Bilateral, 4 x 5 mm (width x depth), one-wall, critical-size, intrabony periodontal defects were surgically created at the mandibular second and fourth pre-molar teeth in five adult Beagle dogs. Defect sites were randomized to receive rhGDF-5/beta-TCP or the rhPDGF construct followed by wound closure for primary intention healing. The animals were sacrificed following an 8-week healing interval for histological and histometric examination. RESULTS: Clinical healing was generally uneventful. Sites receiving rhGDF-5/beta-TCP exhibited a significantly enhanced cementum formation compared with sites receiving the rhPDGF construct, averaging (+/-SD) 4.49+/-0.48 versus 2.72+/-0.91 mm (p<0.001). Similarly, bone regeneration height and area were significantly enhanced at sites receiving rhGDF-5/beta-TCP versus that of the rhPDGF construct averaging, 3.08+/-0.74 versus 1.29+/-0.78 mm (p<0.001) and 6.03+/-1.28 versus 2.98+/-2.61 mm(2) (p<0.01), respectively. Cementum regeneration included cellular/acellular mixed (extrinsic/intrinsic) fibre cementum at sites receiving rhGDF-5/beta-TCP; sites receiving the rhPDGF/beta-TCP showed a pre-dominantly acellular cementum. Newly formed cementum generally extended above the adjoining alveolar bone. Both protocols displayed beta-TCP residues apparently undergoing resorption. Application of both materials appears safe, as they were associated with limited, if any, adverse events. CONCLUSION: rhGDF-5/beta-TCP shows a significant potential to support/accelerate periodontal wound healing/regeneration. Application of rhGDF-5/beta-TCP appears safe and should be further evaluated in human clinical trials.

Periodontal wound healing/regeneration following implantation of recombinant human growth/differentiation factor-5 (rhGDF-5) in an absorbable collagen sponge carrier into one-wall intrabony defects in dogs: a dose-range study.

AIM: Recombinant human growth/differentiation factor-5 (rhGDF-5) is being evaluated as a candidate therapy in support of periodontal regeneration. The objective of this study was to evaluate cementum and alveolar bone formation, and aberrant healing events following surgical implantation of rhGDF-5 in an absorbable collagen sponge (ACS) carrier using an established periodontal defect model. MATERIALS AND METHODS: Bilateral 4 x 5 mm (width x depth), one-wall, critical-size, intrabony periodontal defects were surgically created at the mandibular second and fourth pre-molar teeth in 15 Beagle dogs. Five animals received 1 microg/defect and five animals 20 microg/defect rhGDF-5 in unilateral defect sites. Contralateral sites received treatments reported elsewhere. Five animals received rhGDF-5/ACS with 0 (buffer control) and 100 microg/defect rhGDF-5 in contralateral defect sites. The animals were euthanized at 8 weeks post-surgery for histologic and histometric evaluation. RESULTS: Surgical implantation of rhGDF-5 stimulated significant periodontal regeneration. Cementum formation was significantly enhanced in sites implanted with rhGDF-5 (1 and 100 microg) compared with control (p<0.05). Similarly, bone formation height was significantly greater in sites receiving rhGDF-5 (1 and 100 microg) compared with control (p<0.05). There were no significant or remarkable differences in bone and cementum formation within the selected dose interval (1, 20 and 100 microg rhGDF-5). None of the control or the rhGDF-5 sites exhibited root resorption, ankylosis, or other aberrant tissue reactions. CONCLUSION: Surgical implantation of rhGDF-5/ACS may be used safely to support periodontal wound healing/regeneration in intrabony periodontal defects without complications.

Sinus floor augmentation with recombinant human growth and differentiation factor-5 (rhGDF-5): a pilot study in the Goettingen miniature pig comparing autogenous bone and rhGDF-5.

AIM: The aim of this study was to test the hypothesis that recombinant human growth and differentiation factor-5 (rhGDF-5) in combination with a beta-tricalcium phosphate (beta-TCP) scaffold material results in superior bone formation in sinus floor augmentations in miniature pigs compared with a particulated autogenous bone graft combined with the scaffold material. MATERIAL AND METHODS: Six adult female Goettingen minipigs underwent a maxillary sinus floor augmentation procedure. In a split-mouth design, the sinus floors were augmented with beta-TCP mixed with autogenous cortical bone chips, in a ratio of approximately 1 : 1, on one side. The contralateral test site was augmented using beta-TCP coated with two concentrations of rhGDF-5 (400 microg rhGDF-5/g beta-TCP or 800 microg rhGDF-5/g beta-TCP; three animals in each case). Simultaneously, one dental implant was inserted into each sinus floor augmentation. After 12 weeks, a histological and histomorphometric assessment of non-decalcified histological specimens was made. RESULTS: There were significantly higher mean values of volume density of newly formed bone using beta-TCP coated with two concentrations of rhGDF-5 (400 microg: 32.9%; 800 microg: 23.9%) than with the corresponding control (autogenous bone/beta-TCP) (14.6%, 12.9%) (P=0.012, P=0.049). The bone-to-implant contact rates (BIC) were significantly enhanced in test sites (400 microg: 84.2%; 800 microg: 69.8%) compared with the corresponding control sites (24.8%, 40.8%) (P=.027, P=.045). CONCLUSION: rhGDF-5 delivered on beta-TCP significantly enhanced bone formation compared with beta-TCP combined with autogenous bone in sinus lift procedures in miniature pigs.

The effects of recombinant human growth/differentiation factor-5 (rhGDF-5) on bone regeneration around titanium dental implants in barrier membrane-protected defects: a pilot study in the mandible of beagle dogs.

PURPOSE: This dog study sought to evaluate guided bone regeneration (GBR) in peri-implant defects following implantation of beta-tricalcium phosphate (beta-TCP) with and without osteoinductive recombinant human growth/differentiation factor-5 (rhGDF-5). MATERIALS AND METHODS: In five beagle dogs, all mandibular premolars and the first molar were extracted. After 2 months, six buccolingual critical-size defects were created, and an implant was inserted into the center of each defect. One defect was filled with beta-TCP coated with rhGDF-5 (600 microg/g beta-TCP) and covered with a titanium-reinforced e-PTFE membrane (GDF group). A second defect received the same treatment, but pure uncoated beta-TCP was used (TCP group). A third defect was filled with beta-TCP mixed with autograft and not protected with a membrane (control group). The remaining three defects were filled with other biomaterials. After 2 months, total new bone area, regenerated bone height, and residual amount of beta-TCP were determined histomorphometrically. RESULTS: All implants osseointegrated. One membrane in each group became exposed. Mean new bone area for GDF, TCP, and control sites was 43.9 +/- 18.7 mm2, 32.3 +/- 16.1 mm2, and 13.1 +/- 4.0 mm2, respectively, with a significant difference between GDF and control groups. Mean regenerated bone height was 103.8 +/- 29.7%, 75.4 +/- 36.6%, and 67.2 +/- 19.1% for the GDF, TCP, and control groups, respectively. Mean residual matrix volumes were 25.9 +/- 13.6%, 30.0 +/- 13.0%, and 13.4 +/- 6.5%, respectively. Membrane protection of peri-implant defects filled with beta-TCP resulted in a stronger effect on bone regeneration, although this was not statistically significant. The most pronounced regenerative results were achieved in rhGDF-5/beta-TCP filled membrane-protected defects. CONCLUSION: Delivery of rhGDF-5 on beta-TCP might have the potential to enhance the results of GBR in peri-implant defects.

Development of an injectable composite as a carrier for growth factor-enhanced periodontal regeneration.

AIM: Biomaterials are often applied in periodontal therapy; however, not always well adapted for tissue regeneration. The objective of this study was to evaluate the physico-chemical properties and biocompatibility of an injectable, in situ setting composite for growth factor-enhanced periodontal regeneration. MATERIAL AND METHODS: The composite constitutes bioresorbable poly(lactic-co-glycolic acid) (PLGA) and additives forming in situ a matrix designed as a carrier for recombinant human growth/differentiation factor-5 (rhGDF-5). In vitro characterization included the porosity, biointeraction, biodegradation, injectability, and biological activity of released rhGDF-5. Biocompatibility was compared with granular beta-tricalcium phosphate and an absorbable collagen sponge using a canine periodontal defect model. RESULTS: The PLGA composite showed a highly porous (500-1000 mum) space-providing structure. It effectively induced coagulation exhibiting an intimate interaction with the fibrin clot. The biphasic biodegradation was complete within 4 weeks. The composite was conveniently injectable (90.4+/-3.6 N) for ease of use. It exhibited a sustained rhGDF-5 release over 4 weeks (40.8%) after initial burst (3.4%) detected by ALP activity. Sites receiving the composite showed limited, if any, residuals and had no appreciable negative effect on periodontal wound healing. There were no noteworthy inflammatory lesions in sites receiving the PLGA composite. CONCLUSION: Characteristics of the PLGA composite makes it an attractive matrix to support native wound healing and rhGDF-5-enhanced periodontal regeneration.

Superior effect of MD05, beta-tricalcium phosphate coated with recombinant human growth/differentiation factor-5, compared to conventional bone substitutes in the rat calvarial defect model.

BACKGROUND: MD05 consists of beta-tricalcium phosphate (beta-TCP) coated with recombinant human growth/differentiation factor-5 (rhGDF-5) and is under evaluation as an osteoinductive and osteoconductive bone graft material for use in dental and maxillofacial applications. The objective of this study was to compare the bone regenerative properties of MD05 with those of conventional commercially available bone substitutes. METHODS: Full-thickness, 6-mm diameter, calvarial critical-size defects (two per animal) were created in adult Sprague-Dawley rats. Groups of rats were implanted with the following: 1) MD05; 2) bovine bone mineral; 3) bovine bone mineral with collagen; 4) bovine bone mineral with synthetic peptide, 5) beta-TCP (from two different manufacturers); or 6) no filling material (sham controls). Blinded macroscopic analysis, histopathologic analysis, and histomorphometric analysis were carried out 6 weeks after implantation. RESULTS: New bone formation assessed histomorphometrically was about five times greater with MD05 than with the other bone substitutes tested, and bone repair was well advanced in MD05-filled defects after 6 weeks. The extent of fibrous tissue and residual implant were significantly lower in the MD05 group. In contrast to the other materials, the use of MD05 was associated with the complete osseous bridging of the defect and with the presence of normal bone marrow. The osteoinductive effect of rhGDF-5 was apparent from the more pronounced bone ingrowth observed with MD05 compared to the beta-TCP carrier alone. All implants showed good biocompatibility. CONCLUSION: MD05 achieved superior bone regeneration compared to conventional materials and is a promising new bone substitute for dental and maxillofacial applications.

Tissue distribution and receptor-mediated clearance of anti-CD11a antibody in mice.

Efalizumab (Raptiva) is a humanized monoclonal antibody specific for CD11a, the alpha-chain component of the lymphocyte function-associated antigen 1. In humans, the rate of efalizumab elimination from serum was related to the level of CD11a cell surface expression. These data suggested a role for the CD11a receptor, itself, in efalizumab clearance. Recently, we conducted a series of in vitro studies that suggested a role for CD11a-expressing T cells in efalizumab clearance as mediated by cellular internalization and lysosome-mediated degradation (Coffey et al., 2004). To further study the mechanism of anti-CD11a clearance in vivo, we assessed the tissue distribution, cellular internalization, and subcellular localization of a rat anti-mouse CD11a monoclonal antibody in various tissues in mice. Anti-CD11a antibody primarily distributed to leukocytes and macrophages in the peripheral blood, spleen, and liver, with uptake in the lymph nodes and bone marrow after 72 h. At least a portion of the antibody was internalized and cleared by peripheral blood mononuclear cells, lymphocytes, and splenocytes in a time-dependent manner in vivo. Internalized antibody costained with LysoTracker Red, suggesting that it was transported to lysosomes for degradation. Together, these data suggest that one clearance mechanism for anti-CD11a antibody in vivo is via receptor-mediated internalization and lysosomal degradation by CD11a-expressing cells and tissues.

Evaluation of a surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal antibody.

Surrogate antibodies are a potential solution to the limited safety testing possible with humanized monoclonal antibodies with restricted species cross-reactivity. However, there are currently no defined criteria by which a potential surrogate antibody should be judged prior to its use in determining safety issues for the clinical agent. We propose that, potential surrogates should undergo rigorous evaluation to assess pharmacological and toxicological activities in comparison to the clinical agent. The current studies evaluated a chimeric mouse/rat anti-mouse CD11a monoclonal antibody (muM17) as a potential surrogate for efalizumab, a humanized anti-CD11a antibody in development for psoriasis. CD11a is a subunit of lymphocyte function associated antigen-1, an integrin involved in cell-cell interactions important to immune responses and inflammation. In vitro pharmacology studies included binding affinity to whole mouse blood and inhibitory activity of muM17 in a mixed lymphocyte response assay. In vivo pharmacology was examined using a delayed type hypersensitivity assay in female CD-1 mice. The toxicology evaluation included a murine tissue cross-reactivity study and in vivo multiple dose studies in female CD-1 mice which were administered muM17 (0.1-30 mg/kg) via subcutaneous injections once a week for 4 weeks. Clinical observations, body weight, clinical pathology, T cell CD11a expression, immunogenicity, toxicokinetics, and lymphoid organ histopathology were evaluated. Finally, since reproductive safety testing would be an important application of the proposed surrogate antibody, a pilot study in pregnant mice was conducted that demonstrated proportional transfer of muM17 into the fetus. These studies demonstrated that muM17 has pharmacological and toxicological activities similar to efalizumab. The selection of dose and regimen for GLP (Good Laboratory Practice) toxicology studies and extrapolation to clinical dose levels was based on pharmacodynamic activity (CD11a downmodulation on T cells).