Anti-DKK1 ADCC Enhanced Antibody (BHQ880) is an ADCC enhanced antibody produced by our Afuco™ platform. BHQ880 is a human neutralizing IgG1 anti-DKK1 monoclonal antibody, that is being investigated for its impact on multiple myeloma-related bone disease and as an agent with potential anti-myeloma activity. BHQ880 in combination with zoledronic acid and anti-myeloma therapy was well tolerated and demonstrated potential clinical activity in patients with relapsed or refractory multiple myeloma.
Figure 1 BHQ880 reverses the inhibitory effect of MM cells on osteoblastogenesis.
(A) BMSC obtained from BM aspirate of MM patients were stimulated with OB differentiation media for 3 weeks in the presence of IgG1 isotype control antibody or 1 μg/mL BHQ880 and in the absence (top panel) or in the presence (bottom panel) of INA-6 MM cells. At the end of the culture period, the cells were fixed in 10% formaldehyde and stained with Alizarin Red for 30 minutes. (B) Calcium deposition was quantified in these cultures using osteogenesis assay kit. The amount of calcium deposits in differentiated BMSC treated with BHQ880 (red column) is expressed as percent of calcium deposition compared with differentiated BMSC treated with isotype control antibody (blue column) in the absence and presence of MM cells. (C) Supernatants from these assays were analyzed for huIL-6 level by ELISA. IL-6 production was suppressed after treatment with BHQ880 in supernatants from both cultures with and without MM cells.
Fulciniti,M.,Tassone,P.,Hideshima, T.,Vallet,S.,Nanjappa,P.,Ettenberg,S.A.,& Mitsiades,C.(2009).Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371-379.
Figure 2 BHQ880 overcomes the growth promoting effect of BMSC on both IL-6-dependent and IL-6-independent MM cells.
(A) INA-6 MM cells were cultured without and with BMSC in the presence of different doses of BHQ880 for 24 to 48 hours. Cell proliferation was assessed by [3H]thymidine uptake assay and is presented as percentage change from control. Data represent mean ± SD of 4 independent experiments performed in triplicates. (B) MM1S, OPM1, OPM2, U266, XG1 MM cell lines, and (C) primary cells from 5 MM patients were cultured without (−) and with (+) BMSC in the presence of BHQ880 for 48 hours. Cell proliferation was assessed by [3H]thymidine uptake assay and presented as change from control cells cultured in the absence of BMSC (−). Data represent mean ± SD of 4 independent experiments performed in triplicate.
Fulciniti,M.,Tassone,P.,Hideshima, T.,Vallet,S.,Nanjappa,P.,Ettenberg,S.A.,& Mitsiades,C.(2009).Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371-379.
Figure 3 BHQ880 inhibits IL-6 production and MM cell adhesion to BMSC from MM patients.
(A) Both BMSC from MM patient alone and cocultured with INA-6 cells were treated with isotype control antibody (□) or 1 μg/mL BHQ880 for 24 hours. Culture supernatant was then analyzed for huIL-6 level by ELISA. (B) INA-6 and MM1S MM cells were cultured in the presence of BMSC and increasing concentrations of rIL-6 (0, 0.5, and 1 ng/mL) with and without BHQ880 for 24 hours. Cell proliferation was assessed by [3H]thymidine uptake assay and is presented as percentage change from control. (C) Serum-starved MM cell lines and CD138+ patient MM cells were labeled with calcein AM, washed, and added to BMSC-coated plates for 4 hours with isotype control or increasing amounts of BHQ880 (0.1 and 1 μg/mL). Adhesion was evaluated by measuring the absorbance using 492/520 nm filter set with a fluorescence plate reader. Data represent mean ± SD of 4 independent experiments performed in triplicate.
Fulciniti,M.,Tassone,P.,Hideshima, T.,Vallet,S.,Nanjappa,P.,Ettenberg,S.A.,& Mitsiades,C.(2009).Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371-379.
Figure 4 BHQ880 inhibits IL-6 production and MM cell adhesion and modulates β-catenin and NF-κB pathways in BMSC from MM patients. BMSC were incubated for 24 hours with 1 μg/mL isotype control or BHQ880. Cells were harvested and subjected to cell lysis.
(A) Cytoplasmic fraction was subjected to immunoblotting using anti-phospho β-catenin antibody and anti–β-catenin antibody. (B) Nuclear fraction was subjected to EMSA for NF-κB binding activity. Oct-1 DNA binding activity by EMSA was used as internal control. (C) Nuclear proteins (15 μg) were analyzed for NF-κB activity using the Transcription Factor ELISA kit, which measures DNA binding activity. Absorbance was obtained with a spectrophotometer at 450 nm and is presented as optical density (OD).
Fulciniti,M.,Tassone,P.,Hideshima, T.,Vallet,S.,Nanjappa,P.,Ettenberg,S.A.,& Mitsiades,C.(2009).Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371-379.
Figure 5 BHQ880 improves bone disease in a murine model of human MM. SCID-hu mice were injected with INA-6 cells into the implanted bone and treated with isotype control (n = 7) or BHQ880 (n = 7) after first detection of tumor.
(A) After injection of INA-6 MM cells directly into the human bone implant, serum from SCID-hu mice were monitored for production of DKK1 (blue column) and shuIL-6R (green column) by ELISA. (B) One month after treatment, bone chips were retrieved and decalcified, and sections from control and BHQ880-treated bones were immunohistochemically stained for ALP (top), and the number of OB was measured per field in isotype control and BHQ880-treated bones (bottom). Sections were observed and photographed with a Nikon transmitted light microscope. Original magnification ×200. Data are expressed as ± SD. (C) Serum level of human osteocalcin in murine blood was evaluated at the end of the treatment period by ELISA. Data are expressed as mean ± SD. (D) Sections from control and BHQ880-treated bones were stained by H&E showing increased bone tissue and decreased MM cell number in the BHQ880-treated compared with isotype control-treated samples. Sections were observed and photographed with a Nikon transmitted light microscope. Original magnification ×100.
Fulciniti,M.,Tassone,P.,Hideshima, T.,Vallet,S.,Nanjappa,P.,Ettenberg,S.A.,& Mitsiades,C.(2009).Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371-379.
Figure 6 BHQ880 inhibits myeloma cell growth in SCID-hu mice.
(A) In the early treatment model, mice were injected with isotype control (200 μg per mouse 3×/week; n = 7) and BHQ880 (200 μg per mouse 3×/week; n = 7) at the first detection of tumor. Serum samples were collected weekly, and the level of shuIL-6R was measured by ELISA. (B) In the late treatment model, mice were injected with isotype control (200 μg per mouse 3×/week; n = 3) and BHQ880 (200 μg per mouse 3×/week; n = 3) 3 weeks after first detection of tumor. Serum samples were collected weekly, and the level of shuIL-6R was measured by ELISA. Baseline values before treatment were not significantly different among groups.
Fulciniti,M.,Tassone,P.,Hideshima, T.,Vallet,S.,Nanjappa,P.,Ettenberg,S.A.,& Mitsiades,C.(2009).Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood, 114(2), 371-379.
Figure 7 Bone mineral density by SRE status at baseline and SRE status on study. Lumbar spine and total hip with proximal femur bone mineral density (BMD) were measured by dual energy X-ray absorptiometry scans at baseline and every three cycles thereafter.
(A) Mean percentage change in lumbar spine and total hip with proximal femur BMD in patients with active skeletal-related event (SRE) at baseline. (B) Mean percentage change in lumbar spine BMD by new SRE on study. (C) Mean percentage change in total hip with proximal femur BMD by new SRE on study. BMD, bone mineral density; C, cycle; D, day; EOT, end of treatment; SRE, skeletal-related event.
Iyer,S.P.,Beck,J.T.,Stewart,A.K.,Shah,J.,Kelly,K.R.,Isaacs,R.,& Munshi, N. C. (2014). A Phase IB multicentre dose-determination study of BHQ 880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. British journal of haematology, 167(3), 366-375.
Figure 8 Mean (standard deviation) concentration–time profiles for serum BHQ880 by dose cohort and cycle.
Blood sampling for pharmacokinetic assessments were taken at specified timepoints up to Day 60 and serum levels of BHQ880 were measured using an enzyme-linked immunosorbent assay. Semi-log values of BHQ880 are shown.
Iyer,S.P.,Beck,J.T.,Stewart,A.K.,Shah,J.,Kelly,K.R.,Isaacs,R.,& Munshi, N. C. (2014). A Phase IB multicentre dose-determination study of BHQ 880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events. British journal of haematology, 167(3), 366-375.
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CAT | Product Name | Application | Type |
---|---|---|---|
TAB-214CL | Anti-Human DKK1 Recombinant Antibody (BHQ880) | IHC, ELISA, IB | Antibody |
TAB-195MZ | Human Anti-DKK1 Recombinant Antibody (TAB-195MZ) | In vivo efficacy assay | Human IgG |
TAB-197MZ | Anti-Human DKK1 Recombinant Antibody (RH1-10) | Inhib | Human antibody |
TAB-198MZ | Anti-Human DKK1 Recombinant Antibody (RH2-18) | ELISA, FuncS, Inhib | Human antibody |
TAB-195MZ-S(P) | Human Anti-DKK1 Recombinant Antibody; scFv Fragment (TAB-195MZ-S(P)) | In vivo efficacy assay | Human scFv |
CAT | Product Name | Application | Type |
---|---|---|---|
TAB-192MZ | Anti-Mouse DKK1 Recombinant Antibody (JC18) | ELISA, FuncS | |
TAB-194MZ | Mouse Anti-DKK1 Recombinant Antibody (TAB-194MZ) | ELISA | Mouse IgG |
TAB-196MZ | Rat Anti-DKK1 Recombinant Antibody (TAB-196MZ) | FuncS | Rat IgG |
TAB-192MZ-S(P) | Anti-Mouse DKK1 Recombinant Antibody scFv Fragment (JC18) | ELISA | |
TAB-194MZ-S(P) | Mouse Anti-DKK1 Recombinant Antibody; scFv Fragment (TAB-194MZ-S(P)) | ELISA | Mouse scFv |
CAT | Product Name | Application | Type |
---|---|---|---|
TAB-193MZ | Anti-Human DKK1 Recombinant Antibody (huMabJC18) | ELISA | Humanized antibody |
TAB-193MZ-S(P) | Anti-Human DKK1 Recombinant Antibody scFv Fragment (huMabJC18) | ELISA | Humanized antibody |
TAB-193MZ-F(E) | Anti-Human DKK1 Recombinant Antibody Fab Fragment (huMabJC18) | ELISA | Humanized antibody |
CAT | Product Name | Application | Type |
---|---|---|---|
TAB-010MZ-VHH | Anti-Human DKK1 Recombinant Antibody (1B9) | ELISA | Single domain antibody |
TAB-011MZ-VHH | Anti-Human DKK1 Recombinant Antibody (4E4) | ELISA | Single domain antibody |
TAB-012MZ-VHH | Anti-Human DKK1 Recombinant Antibody (16A12) | ELISA | Single domain antibody |
HPAB-1510-FY | Llama Anti-DKK1 Recombinant Antibody (HPAB-1510-FY) | ELISA | Llama VHH |
HPAB-1511-FY | Llama Anti-DKK1 Recombinant Antibody (HPAB-1511-FY) | ELISA | Llama VHH |
CAT | Product Name | Application | Type |
---|---|---|---|
MOB-0054CT | Recombinant Mouse anti-Human DKK1 Monoclonal antibody (EML1238) | WB | |
HPAB-0278-YC | Human Anti-DKK1 Recombinant Antibody (HPAB-0278-YC) | ELISA, Block, FuncS | Human IgG |
HPAB-0279-YC | Human Anti-DKK1 Recombinant Antibody (HPAB-0279-YC) | Block, FuncS | Human IgG |
HPAB-0280-YC | Human Anti-DKK1 Recombinant Antibody (HPAB-0280-YC) | ELISA | Human IgG |
HPAB-0096-FY | Human Anti-DKK1 Recombinant Antibody (HPAB-0096-FY) | FuncS | Human IgG, κ |
CAT | Product Name | Application | Type |
---|---|---|---|
NEUT-703CQ | Rabbit Anti-DKK1 Recombinant Antibody (clone CBL1003) | Neut | Rabbit IgG |
CAT | Product Name | Application | Type |
---|---|---|---|
MOR-0991 | Hi-Affi™ Rabbit Anti-DKK1 Recombinant Antibody (clone DS991AB) | FC, ICC, IF, IHC-P, WB | Rabbit IgG |
MOR-4137 | Hi-Affi™ Rabbit Anti-DKK1 Recombinant Antibody (clone SI210DS) | Neut | Rabbit IgG |
CAT | Product Name | Application | Type |
---|---|---|---|
HPAB-0278-YC-S(P) | Human Anti-DKK1 Recombinant Antibody; scFv Fragment (HPAB-0278-YC-S(P)) | ELISA, Block, FuncS | Human scFv |
HPAB-0279-YC-S(P) | Human Anti-DKK1 Recombinant Antibody; scFv Fragment (HPAB-0279-YC-S(P)) | Block, FuncS | Human scFv |
HPAB-0280-YC-S(P) | Human Anti-DKK1 Recombinant Antibody; scFv Fragment (HPAB-0280-YC-S(P)) | ELISA | Human scFv |
HPAB-670-FY-S(P) | Human Anti-DKK1 Recombinant Antibody; scFv Fragment (HPAB-670-FY-S(P)) | ELISA | Human scFv |
HPAB-0757-FY-F(E) | Mouse Anti-DKK1 Recombinant Antibody; Fab Fragment (HPAB-0757-FY-F(E)) | ELISA | Mouse Fab |
CAT | Product Name | Application | Type |
---|---|---|---|
HPAB-0278-YC-F(E) | Human Anti-DKK1 Recombinant Antibody; Fab Fragment (HPAB-0278-YC-F(E)) | ELISA, Block, FuncS | Human Fab |
HPAB-0279-YC-F(E) | Human Anti-DKK1 Recombinant Antibody; Fab Fragment (HPAB-0279-YC-F(E)) | Block, FuncS | Human Fab |
HPAB-0280-YC-F(E) | Human Anti-DKK1 Recombinant Antibody; Fab Fragment (HPAB-0280-YC-F(E)) | ELISA | Human Fab |
HPAB-0096-FY-F(E) | Human Anti-DKK1 Recombinant Antibody; Fab Fragment (HPAB-0096-FY-F(E)) | FuncS | Human Fab |
HPAB-0107-FY-F(E) | Human Anti-DKK1 Recombinant Antibody; Fab Fragment (HPAB-0107-FY-F(E)) | FuncS | Human Fab |
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