Major histocompatibility complex (MHC)-Associated Peptide Proteomics (MAPPs) is an ex vivo method... more Major histocompatibility complex (MHC)-Associated Peptide Proteomics (MAPPs) is an ex vivo method used to assess the immunogenicity risk of biotherapeutics. MAPPs can identify potential T-cell epitopes within the biotherapeutic molecule. Using adalimumab treated human monocyte derived dendritic cells (DCs) and a pan anti-HLA-DR antibody (Ab), we systematically automated and optimized biotin/streptavidin (SA)-capture antibody coupling, lysate incubation with capture antibody, as well as the washing and elution steps of a MAPPs method using functionalized magnetic beads and a KingFisher Magnetic Particle processor. Automation of these steps, combined with capturing using biotinylated-Ab/SA magnetic beads rather than covalently bound antibody, improved reproducibility as measured by minimal inter-and intra-day variability, as well as minimal analyst-to-analyst variability. The semi-automated MAPPs workflow improved sensitivity, allowing for a lower number of cells per analysis. The met...
Journal of the American Society for Mass Spectrometry, Apr 1, 2006
Chemokines play a critical role in inducing chemotaxis, extravasation, and activation of leukocyt... more Chemokines play a critical role in inducing chemotaxis, extravasation, and activation of leukocytes both in routine immunosurveillance and autoimmune diseases. Traditionally, to disrupt chemokine function, strategies have focused on blockage of its interaction with the receptor. Recently, it has been demonstrated that binding to glycosaminoglycans (GAGs) is also required for the in vivo activity of many chemokines. Thus, interference with the GAG-binding of chemokines may offer an alternative, valid, anti-inflammatory strategy. However, the potential of using small polyanions to inhibit the interactions between chemokines and cell surface GAGs has not been fully explored. In this study, a mass spectrometry based filtration trapping assay was utilized to study the interactions between two CCR 2 ligands (MCP-1/CCL2 and MCP-3/CCL7) and a series of low molecular weight, polyanionic molecules. Findings were confirmed by using a hydrophobic trapping assay. The results indicated that Arixtra (fondaparinux sodium), sucrose octasulfate, and suramin were specific binders of the chemokines, while cyclodextrin sulfate, although the most highly sulfated molecule among the ones investigated, showed no binding. The binding stoichiometry of the small molecule ligand was determined from the measured molecular weight of the noncovalent complex. Furthermore, the dissociation constant between MCP-3 and Arixtra was determined by using electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) mass spectrometry, which compared favorably with the result of the isothermal titration calorimetry (ITC) assay. The relative binding affinity of these ligands to MCP-3 was also determined using a competitive filtration trapping assay.
Purpose: Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprising the cytotox... more Purpose: Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker. Thrombocytopenia was the dose-limiting toxicity in the phase I study, and grade ≥3 thrombocytopenia occurred in up to 13% of patients receiving T-DM1 in phase III studies. We investigated the mechanism of T-DM1–induced thrombocytopenia.Experimental Design: The effect of T-DM1 on platelet function was measured by aggregometry, and by flow cytometry to detect the markers of activation. The effect of T-DM1 on differentiation and maturation of megakaryocytes (MK) from human hematopoietic stem cells was assessed by flow cytometry and microscopy. Binding, uptake, and catabolism of T-DM1 in MKs, were assessed by various techniques including fluorescence microscopy, scintigraphy to detect T-[H3]-DM1 and 125I-T-DM1, and mass spectrometry. The role of FcγRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab tha...
BackgroundTrastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody–drug conjugate (ADC) in devel... more BackgroundTrastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody–drug conjugate (ADC) in development for the treatment of HER2-postive MBC. T-DM1 is composed of trastuzumab (Herceptin®), DM1, an inhibitor of tubulin polymerization derived from maytansine, and the stable MCC linker that conjugates DM1 and trastuzumab. T-DM1 has been tested at multiple dose levels in a Phase I trial: q3w (0.3–4.8 mg/kg) and weekly (1.2–2.9 mg/kg), and in two subsequent Phase II trials with T-DM1 administered as a single agent at 3.6 mg/kg q3w. A population pharmacokinetic (PK) model for T-DM1 conjugate was developed using pooled PK data from these trials to estimate typical PK parameter values and inter-patient variability in patients with HER2-positive MBC. The model was further developed to explore and quantify the effect of body size and pathophysiologic covariates on the pharmacokinetics of T-DM1 to better understand the clinical factors that might affect safety for individual patients.MethodsF...
Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab mono... more Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to character...
Figure S7. Histology of primary breast cancer tissue. Representative pictures of CAV1 levels in d... more Figure S7. Histology of primary breast cancer tissue. Representative pictures of CAV1 levels in different TMA cores from primary breast cancer showing (A) DCIS and stroma (B, C) invasive tumor cells, fat tissue, and stroma. The CAV1 levels are higher in myoepithelial cells than in luminal cells. The scale bare corresponds to 20 µm.
Supplementary Table 1. Patient and tumor characteristics in relation to tumor-specific cytoplasmi... more Supplementary Table 1. Patient and tumor characteristics in relation to tumor-specific cytoplasmic intensity of CAV1
Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emta... more Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a novel HER2 ADC, we selected an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. We modified the PBD dimer to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrated in vivo efficacy in models of HER2-positive and HER2-low cancers and was well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study in patients with HER2-positive metastatic breast cancer showed early signs of anti-tumor activity with limited toxicity. However, delayed dermal, ocular and pulmonary toxicities developed. The delayed onset, as well as non-resolva...
Supplementary Methods, Figures S1-S7 Suppl. Fig. S1, Differentiation of hematopoietic stem cells ... more Supplementary Methods, Figures S1-S7 Suppl. Fig. S1, Differentiation of hematopoietic stem cells (CD133+/CD34+) into immature megakarytocytes Suppl. Fig. S2, T-DM1 does not directly induce platelet aggregation in washed platelets Suppl. Fig. S3, At high concentrations, DM1 inhibits agonist-induced platelet aggregation in platelet-rich plasma Suppl. Fig. S4, DM1 conjugates alter the morphology of megakaryocytes Suppl. Fig. S5, Uptake of T-[3H]DM1 varies by differentiation stage Suppl. Fig. S6, HER2 is not expressed on megakaryocytes or platelets Suppl. Fig. S7, Prolonged exposure to T-DM1 results in disruption of cytoskeletal structure in maturing megakaryocytes
Background: Many HER2-directed antibody-drug conjugates (ADCs) in early development employ trastu... more Background: Many HER2-directed antibody-drug conjugates (ADCs) in early development employ trastuzumab linked to tubulin binding agents as the cytotoxic drug. DHES0815A is an ADC consisting of a THIOMABTM humanized IgG1 anti-HER2 monoclonal antibody (hu7C2), which binds domain 1 of the HER2 ECD, conjugated via a disulfide linker to PBD-monoamide (MA), a DNA mono-alkylating agent. The reduced potency of the PBD-MA payload compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of hu7C2 to a HER2 epitope distinct from trastuzumab and pertuzumab allows combination with existing HER2 therapies. . Methods: Modifications at one imine in the PBD (pyrrolobenzodiazepine) dimer produced mono-alkylating PBDs that were assessed for DNA binding, permeability and cell potency. Each modified PBD was conjugated to hu7C2 LC K149C via a disulfide linker and assessed in HER2-positive models in vitro and in vivo. Safety stud...
Almost every major world religion and tribal spiritualities light plant parts in worship to seek ... more Almost every major world religion and tribal spiritualities light plant parts in worship to seek greater connection to the divine. Incense is defined as a material that is burned to produce an odour which is also referred to as the perfume itself that is produced from the burning of plant. Many people light incense sticks in their homes just for the sweet smell and the ability it has to transform space. Others too in our world today may have a stigma connecting incense sticks and illegal drug use. Many of us who have been Catholics may have witnessed the swinging of censers, filling the Church with sweet-smelling resins. The tradition of using incense in the liturgy goes back to ancient Hebrew worship, as recorded in the Psalms: "Let my prayer be set forth in Thy sight as the incense" (Ps 141:2). Incense as often used as part of a purification ritual seems to have lost its symbolisms and proper use of it in the Church as well as the decline of its use. The real problem here is that many faithful hardly know the real reason and purpose why incense is an important part of the Catholic Mass. Do people fully understand the use and symbolism of incense during the liturgical celebrations? Do the traditional use of incense offers some opportunities or challenges in the Church liturgical rites? The purpose of this study is to investigate, stimulate and sensitize the Church and all the Christian faithful of the symbolism of incense which have become optional or none use and to take effective action in reclaiming the lost symbolism and proper use of incense. Perhaps a better understanding of the traditional use of incense may help or enhance the use and importance of the symbolism of incense in our liturgical celebrations. Maybe some elements found in the traditional use of incense, the Sacred Scripture and the Church's practice may enrich and recover the lost symbolism of incense. And may be by organizing Liturgical Seminars/workshops to seminarians and young religious in formation houses it may address the essential elements in the way incense is use. The Traditional Use of "Incensi" among the Annang People: Liturgical Opportunities and Challenges in Ikot Ekpene Catholic Diocese, Nigeria IJSSHR, Volume 04 Issue 12 December 2021 www.ijsshr.in 1. The Traditional Use of "Incensi" among the Annang People Nigeria has 9 Archdioceses and 46 Dioceses which forms the Nine Ecclesiastical Provinces of Abuja (8 Dioceses), Kaduna (7 Dioceses), Benin (6 Dioceses), Lagos (3 Dioceses), Onitsha (7 Dioceses), Owerri (6 Dioceses), Ibadan (6 Dioceses), Jos (7 Dioceses), and Calabar (5 Dioceses) of which Ikot Ekpene is one. Ikot Ekpene Diocese is located in the southern part of Nigeria. It is one of the Dioceses under the suffragan of the Metropolitan of the Calabar Ecclesiastical Province of Calabar since 1 st March 1963. It covers an area of 2,263km 2 (874 sq mi) and has a population of about 908,026 inhabitants of which about 80% are Christians and about 11% of the population are Catholic (2004 Census).
C155 Effective antibody drug conjugates (ADCs), which are monoclonal antibodies linked to potent ... more C155 Effective antibody drug conjugates (ADCs), which are monoclonal antibodies linked to potent cell-killing drugs, require binding to antigen, cellular uptake of the conjugate and ultimately release of the cytotoxin through cleavage of the linker. The rate at which the linker is cleaved, both within the cell and in the serum, may have implications on the toxicity and efficacy of the drug conjugate. To explore this, we conducted studies in the Sprague Dawley rat to characterize the complete disposition of trastuzumab-MCC-DM1, a humanized monoclonal antibody against the Her2 antigen conjugated to the maytansine derivative, DM1, through a non-disulfide linker. Following administration of trastuzumab-MCC-DM1 as a single-dose IV bolus in rats, serum or plasma concentrations of the trastuzumab-MCC-DM1, total trastuzumab, MCC-DM1, and DM1 were determined. In separate studies, MCC-DM1 and DM1 were also administered as single IV boluses to rats and were analyzed for all known analytes. T...
Major histocompatibility complex (MHC)-Associated Peptide Proteomics (MAPPs) is an ex vivo method... more Major histocompatibility complex (MHC)-Associated Peptide Proteomics (MAPPs) is an ex vivo method used to assess the immunogenicity risk of biotherapeutics. MAPPs can identify potential T-cell epitopes within the biotherapeutic molecule. Using adalimumab treated human monocyte derived dendritic cells (DCs) and a pan anti-HLA-DR antibody (Ab), we systematically automated and optimized biotin/streptavidin (SA)-capture antibody coupling, lysate incubation with capture antibody, as well as the washing and elution steps of a MAPPs method using functionalized magnetic beads and a KingFisher Magnetic Particle processor. Automation of these steps, combined with capturing using biotinylated-Ab/SA magnetic beads rather than covalently bound antibody, improved reproducibility as measured by minimal inter-and intra-day variability, as well as minimal analyst-to-analyst variability. The semi-automated MAPPs workflow improved sensitivity, allowing for a lower number of cells per analysis. The met...
Journal of the American Society for Mass Spectrometry, Apr 1, 2006
Chemokines play a critical role in inducing chemotaxis, extravasation, and activation of leukocyt... more Chemokines play a critical role in inducing chemotaxis, extravasation, and activation of leukocytes both in routine immunosurveillance and autoimmune diseases. Traditionally, to disrupt chemokine function, strategies have focused on blockage of its interaction with the receptor. Recently, it has been demonstrated that binding to glycosaminoglycans (GAGs) is also required for the in vivo activity of many chemokines. Thus, interference with the GAG-binding of chemokines may offer an alternative, valid, anti-inflammatory strategy. However, the potential of using small polyanions to inhibit the interactions between chemokines and cell surface GAGs has not been fully explored. In this study, a mass spectrometry based filtration trapping assay was utilized to study the interactions between two CCR 2 ligands (MCP-1/CCL2 and MCP-3/CCL7) and a series of low molecular weight, polyanionic molecules. Findings were confirmed by using a hydrophobic trapping assay. The results indicated that Arixtra (fondaparinux sodium), sucrose octasulfate, and suramin were specific binders of the chemokines, while cyclodextrin sulfate, although the most highly sulfated molecule among the ones investigated, showed no binding. The binding stoichiometry of the small molecule ligand was determined from the measured molecular weight of the noncovalent complex. Furthermore, the dissociation constant between MCP-3 and Arixtra was determined by using electrospray ionization Fourier transform ion cyclotron resonance (ESI FT-ICR) mass spectrometry, which compared favorably with the result of the isothermal titration calorimetry (ITC) assay. The relative binding affinity of these ligands to MCP-3 was also determined using a competitive filtration trapping assay.
Purpose: Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprising the cytotox... more Purpose: Trastuzumab-emtansine (T-DM1) is an antibody–drug conjugate (ADC) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker. Thrombocytopenia was the dose-limiting toxicity in the phase I study, and grade ≥3 thrombocytopenia occurred in up to 13% of patients receiving T-DM1 in phase III studies. We investigated the mechanism of T-DM1–induced thrombocytopenia.Experimental Design: The effect of T-DM1 on platelet function was measured by aggregometry, and by flow cytometry to detect the markers of activation. The effect of T-DM1 on differentiation and maturation of megakaryocytes (MK) from human hematopoietic stem cells was assessed by flow cytometry and microscopy. Binding, uptake, and catabolism of T-DM1 in MKs, were assessed by various techniques including fluorescence microscopy, scintigraphy to detect T-[H3]-DM1 and 125I-T-DM1, and mass spectrometry. The role of FcγRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab tha...
BackgroundTrastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody–drug conjugate (ADC) in devel... more BackgroundTrastuzumab-DM1 (T-DM1) is a first-in-class HER2 antibody–drug conjugate (ADC) in development for the treatment of HER2-postive MBC. T-DM1 is composed of trastuzumab (Herceptin®), DM1, an inhibitor of tubulin polymerization derived from maytansine, and the stable MCC linker that conjugates DM1 and trastuzumab. T-DM1 has been tested at multiple dose levels in a Phase I trial: q3w (0.3–4.8 mg/kg) and weekly (1.2–2.9 mg/kg), and in two subsequent Phase II trials with T-DM1 administered as a single agent at 3.6 mg/kg q3w. A population pharmacokinetic (PK) model for T-DM1 conjugate was developed using pooled PK data from these trials to estimate typical PK parameter values and inter-patient variability in patients with HER2-positive MBC. The model was further developed to explore and quantify the effect of body size and pathophysiologic covariates on the pharmacokinetics of T-DM1 to better understand the clinical factors that might affect safety for individual patients.MethodsF...
Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab mono... more Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to character...
Figure S7. Histology of primary breast cancer tissue. Representative pictures of CAV1 levels in d... more Figure S7. Histology of primary breast cancer tissue. Representative pictures of CAV1 levels in different TMA cores from primary breast cancer showing (A) DCIS and stroma (B, C) invasive tumor cells, fat tissue, and stroma. The CAV1 levels are higher in myoepithelial cells than in luminal cells. The scale bare corresponds to 20 µm.
Supplementary Table 1. Patient and tumor characteristics in relation to tumor-specific cytoplasmi... more Supplementary Table 1. Patient and tumor characteristics in relation to tumor-specific cytoplasmic intensity of CAV1
Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emta... more Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a novel HER2 ADC, we selected an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. We modified the PBD dimer to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrated in vivo efficacy in models of HER2-positive and HER2-low cancers and was well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study in patients with HER2-positive metastatic breast cancer showed early signs of anti-tumor activity with limited toxicity. However, delayed dermal, ocular and pulmonary toxicities developed. The delayed onset, as well as non-resolva...
Supplementary Methods, Figures S1-S7 Suppl. Fig. S1, Differentiation of hematopoietic stem cells ... more Supplementary Methods, Figures S1-S7 Suppl. Fig. S1, Differentiation of hematopoietic stem cells (CD133+/CD34+) into immature megakarytocytes Suppl. Fig. S2, T-DM1 does not directly induce platelet aggregation in washed platelets Suppl. Fig. S3, At high concentrations, DM1 inhibits agonist-induced platelet aggregation in platelet-rich plasma Suppl. Fig. S4, DM1 conjugates alter the morphology of megakaryocytes Suppl. Fig. S5, Uptake of T-[3H]DM1 varies by differentiation stage Suppl. Fig. S6, HER2 is not expressed on megakaryocytes or platelets Suppl. Fig. S7, Prolonged exposure to T-DM1 results in disruption of cytoskeletal structure in maturing megakaryocytes
Background: Many HER2-directed antibody-drug conjugates (ADCs) in early development employ trastu... more Background: Many HER2-directed antibody-drug conjugates (ADCs) in early development employ trastuzumab linked to tubulin binding agents as the cytotoxic drug. DHES0815A is an ADC consisting of a THIOMABTM humanized IgG1 anti-HER2 monoclonal antibody (hu7C2), which binds domain 1 of the HER2 ECD, conjugated via a disulfide linker to PBD-monoamide (MA), a DNA mono-alkylating agent. The reduced potency of the PBD-MA payload compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of hu7C2 to a HER2 epitope distinct from trastuzumab and pertuzumab allows combination with existing HER2 therapies. . Methods: Modifications at one imine in the PBD (pyrrolobenzodiazepine) dimer produced mono-alkylating PBDs that were assessed for DNA binding, permeability and cell potency. Each modified PBD was conjugated to hu7C2 LC K149C via a disulfide linker and assessed in HER2-positive models in vitro and in vivo. Safety stud...
Almost every major world religion and tribal spiritualities light plant parts in worship to seek ... more Almost every major world religion and tribal spiritualities light plant parts in worship to seek greater connection to the divine. Incense is defined as a material that is burned to produce an odour which is also referred to as the perfume itself that is produced from the burning of plant. Many people light incense sticks in their homes just for the sweet smell and the ability it has to transform space. Others too in our world today may have a stigma connecting incense sticks and illegal drug use. Many of us who have been Catholics may have witnessed the swinging of censers, filling the Church with sweet-smelling resins. The tradition of using incense in the liturgy goes back to ancient Hebrew worship, as recorded in the Psalms: "Let my prayer be set forth in Thy sight as the incense" (Ps 141:2). Incense as often used as part of a purification ritual seems to have lost its symbolisms and proper use of it in the Church as well as the decline of its use. The real problem here is that many faithful hardly know the real reason and purpose why incense is an important part of the Catholic Mass. Do people fully understand the use and symbolism of incense during the liturgical celebrations? Do the traditional use of incense offers some opportunities or challenges in the Church liturgical rites? The purpose of this study is to investigate, stimulate and sensitize the Church and all the Christian faithful of the symbolism of incense which have become optional or none use and to take effective action in reclaiming the lost symbolism and proper use of incense. Perhaps a better understanding of the traditional use of incense may help or enhance the use and importance of the symbolism of incense in our liturgical celebrations. Maybe some elements found in the traditional use of incense, the Sacred Scripture and the Church's practice may enrich and recover the lost symbolism of incense. And may be by organizing Liturgical Seminars/workshops to seminarians and young religious in formation houses it may address the essential elements in the way incense is use. The Traditional Use of "Incensi" among the Annang People: Liturgical Opportunities and Challenges in Ikot Ekpene Catholic Diocese, Nigeria IJSSHR, Volume 04 Issue 12 December 2021 www.ijsshr.in 1. The Traditional Use of "Incensi" among the Annang People Nigeria has 9 Archdioceses and 46 Dioceses which forms the Nine Ecclesiastical Provinces of Abuja (8 Dioceses), Kaduna (7 Dioceses), Benin (6 Dioceses), Lagos (3 Dioceses), Onitsha (7 Dioceses), Owerri (6 Dioceses), Ibadan (6 Dioceses), Jos (7 Dioceses), and Calabar (5 Dioceses) of which Ikot Ekpene is one. Ikot Ekpene Diocese is located in the southern part of Nigeria. It is one of the Dioceses under the suffragan of the Metropolitan of the Calabar Ecclesiastical Province of Calabar since 1 st March 1963. It covers an area of 2,263km 2 (874 sq mi) and has a population of about 908,026 inhabitants of which about 80% are Christians and about 11% of the population are Catholic (2004 Census).
C155 Effective antibody drug conjugates (ADCs), which are monoclonal antibodies linked to potent ... more C155 Effective antibody drug conjugates (ADCs), which are monoclonal antibodies linked to potent cell-killing drugs, require binding to antigen, cellular uptake of the conjugate and ultimately release of the cytotoxin through cleavage of the linker. The rate at which the linker is cleaved, both within the cell and in the serum, may have implications on the toxicity and efficacy of the drug conjugate. To explore this, we conducted studies in the Sprague Dawley rat to characterize the complete disposition of trastuzumab-MCC-DM1, a humanized monoclonal antibody against the Her2 antigen conjugated to the maytansine derivative, DM1, through a non-disulfide linker. Following administration of trastuzumab-MCC-DM1 as a single-dose IV bolus in rats, serum or plasma concentrations of the trastuzumab-MCC-DM1, total trastuzumab, MCC-DM1, and DM1 were determined. In separate studies, MCC-DM1 and DM1 were also administered as single IV boluses to rats and were analyzed for all known analytes. T...
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