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1.
Cancer Immunol Immunother ; 65(10): 1169-75, 2016 10.
Article in English | MEDLINE | ID: mdl-27506529

ABSTRACT

In this study, HB22.7, an anti-CD22 monoclonal antibody, was used for specific, targeted delivery of monomethyl auristatin E (MMAE) to non-Hodgkin lymphoma (NHL). MMAE was covalently coupled to HB22.7 through a valine-citrulline peptide linker (vc). Maleimide-functionalized vcMMAE (mal-vcMMAE) was reacted with thiols of the partially reduced mAb. Approximately 4 molecules of MMAE were conjugated to HB22.7 as determined by residual thiol measurement and hydrophobic interaction chromatography-HPLC (HIC-HPLC). HB22.7-vcMMAE antibody-drug conjugate (ADC) retained its binding to Ramos NHL cells and also exhibited potent and specific in vitro cytotoxicity on a panel of B cell NHL cell lines with IC50s of 20-284 ng/ml. HB22.7-vcMMAE also showed potent efficacy in vivo against established NHL xenografts using the DoHH2 and Granta 519 cell lines. One dose of the ADC induced complete and persistent response in all DoHH2 xenografts and 90 % of Granta xenografts. Minimal toxicity was observed. In summary, HB22.7-vcMMAE is an effective ADC that should be evaluated for clinical translation.


Subject(s)
Antibodies, Monoclonal/therapeutic use , B-Lymphocytes/drug effects , Immunotherapy/methods , Immunotoxins/therapeutic use , Lymphoma, Non-Hodgkin/therapy , Oligopeptides/therapeutic use , Animals , Antibodies, Monoclonal/chemistry , Apoptosis , B-Lymphocytes/immunology , Cell Line, Tumor , Female , Immunotoxins/chemistry , Lymphoma, Non-Hodgkin/immunology , Mice , Mice, Inbred ICR , Mice, SCID , Oligopeptides/chemistry , Sialic Acid Binding Ig-like Lectin 2/immunology , Xenograft Model Antitumor Assays
2.
ACS Comb Sci ; 18(6): 320-9, 2016 06 13.
Article in English | MEDLINE | ID: mdl-27053324

ABSTRACT

Identifying "druggable" targets and their corresponding therapeutic agents are two fundamental challenges in drug discovery research. The one-bead-one-compound (OBOC) combinatorial library method has been developed to discover peptides or small molecules that bind to a specific target protein or elicit a specific cellular response. The phage display cDNA expression proteome library method has been employed to identify target proteins that interact with specific compounds. Here, we combined these two high-throughput approaches, efficiently interrogated approximately 10(13) possible molecular interactions, and identified 91 small molecule compound beads that interacted strongly with the phage library. Of 19 compounds resynthesized, 4 were cytotoxic against cancer cells; one of these compounds was found to interact with EIF5B and inhibit protein translation. As more binding pairs are confirmed and evaluated, the "library-against-library" screening approach and the resulting small molecule-protein domain interaction database may serve as a valuable tool for basic research and drug development.


Subject(s)
Drug Discovery/methods , Peptide Library , Proteomics/methods , Small Molecule Libraries , Antineoplastic Agents/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Cell Cycle , Cell Line , Combinatorial Chemistry Techniques/methods , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Drug Screening Assays, Antitumor , High-Throughput Screening Assays , Humans , Jurkat Cells , Ligands , Methionine/metabolism
3.
Leuk Res ; 37(1): 83-8, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23040543

ABSTRACT

Targeted therapies, such as those using imatinib and rituximab, have revolutionized the treatment of Philadelphia chromosome-positive and CD20-positive acute lymphoblastic leukemia (ALL) respectively, yet these therapies are effective in only a subset of patients and remission is generally not durable. The next generation of targeted therapies includes the use of antibodies conjugated to potent cytotoxic agents and are classified as antibody drug conjugates (ADC). For B-lineage ALL, CD22 is an ideal target for ADC therapy because it is expressed on the majority of B-lineage ALL cells and because antibody binding mediates receptor internalization. HB22.7-SAP is a conjugate of our anti-CD22 monoclonal antibody (mAb), HB22.7, and the ribosome inhibiting protein, saporin (SAP). In vitro, HB22.7-SAP effectively bound to CD22 on the surface of pre-B ALL cell lines and exhibited potent and specific cytotoxicity. In a NOD/SCID xenograft mouse model of pre-B ALL, when compared to the vehicle-treated control, HB22.7-SAP increased the median survival time from 20 days to over 50 days without significant toxicity.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunotoxins/therapeutic use , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Ribosome Inactivating Proteins, Type 1/therapeutic use , Sialic Acid Binding Ig-like Lectin 2/antagonists & inhibitors , Animals , Female , Humans , Mice , Mice, SCID , Neoplasm Transplantation , Saporins , Transplantation, Heterologous
4.
Oncoimmunology ; 1(9): 1469-1475, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23264893

ABSTRACT

Antibody drug conjugates (ADCs) can deliver potent drugs to cancer cells by employing the specificity of monoclonal antibodies (mAbs). ADCs have demonstrated significant anticancer activity and, in 2011, brentuximab vedotin has been approved by the FDA for the treatment of Hodgkin's and anaplastic large cell lymphomas. CD22 is an ideal target for ADC against B-cell malignancies because of its lineage-specific expression and rapid internalization upon antibody binding. In this study, we evaluated the anti-CD22 mAb HB22.7 as a vehicle for the targeted delivery of the potent toxin saporin (SAP). In vitro, HB22.7-SAP was cytotoxic against a panel of non-Hodgkin's lymphoma (NHL) cell lines representing the most common types of the disease. Moreover, in a xenograft model of NHL, HB22.7-SAP significantly inhibited the growth of established lesions and completely prevented tumor development when treatment was initiated within 24 h from tumor-cell inoculation. HB22.7-SAP had no significant in vivo toxicity. In conclusion, HB22.7 constitutes a potential platform for CD22-targeted ADCs.

5.
Cancer Res ; 72(21): 5556-65, 2012 Nov 01.
Article in English | MEDLINE | ID: mdl-22986740

ABSTRACT

Most patients with lung cancer still die from their disease, necessitating additional options to improve treatment. Here, we provide evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that we found is also widely expressed in lung cancer cells. In characterizing the antitumor activity of an established anti-CD22 monoclonal antibody (mAb), HB22.7, we showed CD22 expression by multiple approaches in various lung cancer subtypes, including 7 of 8 cell lines and a panel of primary patient specimens. HB22.7 displayed in vitro and in vivo cytotoxicity against CD22-positive human lung cancer cells and tumor xenografts. In a model of metastatic lung cancer, HB22.7 inhibited the development of pulmonary metastasis and extended overall survival. The finding that CD22 is expressed on lung cancer cells is significant in revealing a heretofore unknown mechanism of tumorigenesis and metastasis. Our work suggests that anti-CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets.


Subject(s)
Antibodies, Monoclonal/pharmacology , Lung Neoplasms/metabolism , Sialic Acid Binding Ig-like Lectin 2/biosynthesis , Animals , Blotting, Northern , Blotting, Western , Female , Flow Cytometry , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , RNA, Small Interfering , Real-Time Polymerase Chain Reaction , Transfection , Xenograft Model Antitumor Assays
6.
Mol Pharm ; 9(6): 1727-35, 2012 Jun 04.
Article in English | MEDLINE | ID: mdl-22530955

ABSTRACT

Vincristine (VCR) is a potent anticancer drug, but its clinical efficacy is limited by neurotoxicity. The field of drug delivery may provide an opportunity to increase the therapeutic index of VCR by delivering the drug specifically to tumor sites while sparing normal tissue. We have recently developed a telodendrimer (PEG(5k)-Cys(4)-L(8)-CA(8)) capable of forming disulfide cross-linked micelles (DCMs) which can encapsulate a variety of chemotherapeutics. In the present study, we encapsulated VCR into these micelles (DCM-VCR) and used them to treat lymphoma bearing mice. DCM-VCR particles have a size of 16 nm, which has been shown to be optimal for their accumulation into tumor via the enhanced permeability and retention (EPR) effect. Compared to our first-generation non-cross-linked micelles (NCMs), DCM-VCR demonstrated greater stability and slower drug release under physiological conditions. In addition, DCM-VCR exhibited a maximum tolerated dose (MTD) of 3.5 mg/kg while the MTD for conventional VCR was only 1.5 mg/kg. Using a near-infrared cyanine dye (DiD) as the surrogate drug, we showed that DCM-VCR accumulated at the tumor site starting 1 h after injection and persisted up to 72 h in lymphoma xenografted nude mice. In an in vivo efficacy study, high dose (2.5 mg/kg) DCM-VCR produced the greatest reduction in tumor volume. High dose DCM-VCR was well tolerated with no significant changes in complete blood count, serum chemistry and histology of the sciatic nerve. Mice treated with an equivalent dose (1 mg/kg) of conventional VCR and DCM-VCR controlled tumor growth equally; however, in combination with on-demand addition of the reducing agent N-acetylcysteine, DCM-VCR exhibited a superior antitumor effect compared to conventional VCR.


Subject(s)
Disulfides/chemistry , Lymphoma, B-Cell/drug therapy , Micelles , Vincristine/administration & dosage , Vincristine/therapeutic use , Animals , Cell Line, Tumor , Female , Humans , Mice , Mice, Nude
7.
Biomaterials ; 32(27): 6633-45, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21658763

ABSTRACT

To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross-linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti-tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N-acetylcysteine, after PTX-DCMs have reached the tumor site.


Subject(s)
Cross-Linking Reagents/chemistry , Disulfides/chemistry , Drug Delivery Systems/methods , Micelles , Paclitaxel/administration & dosage , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Death/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Chemical Phenomena/drug effects , Disease Models, Animal , Disulfides/toxicity , Female , Hemolysis/drug effects , Humans , Kinetics , Mice , Mice, Nude , Models, Biological , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Particle Size , Spectroscopy, Near-Infrared , Tissue Distribution/drug effects , Xenograft Model Antitumor Assays
8.
Cancer Immunol Immunother ; 60(6): 771-80, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21347809

ABSTRACT

Previous studies have shown that bispecific antibodies that target both CD20 and CD22 have in vivo lymphomacidal properties. We developed a CD20-CD22 bispecific antibody (Bs20x22) from anti-CD20 and the anti-CD22 monoclonal antibodies (mAb), rituximab and HB22.7, respectively. Bs20x22 was constructed using standard methods and was shown to specifically bind CD20 and CD22. In vitro cytotoxicity assays showed that Bs20x22 was three times more effective than either parent mAb alone and twice as effective as a combination of both parent mAb used at equimolar concentrations. Bs20x22 was also nearly four times more effective at inducing apoptosis than either mAb alone. Examination of the MAPK and SAPK signaling cascades revealed that Bs20x22 induced significantly more p38 phosphorylation than either mAb alone. In an in vivo human NHL xenograft model, treatment with Bs20x22 resulted in significantly greater tumor shrinkage and improved overall survival when compared to either mAb alone or treatment with a combination of HB22.7 and rituximab. The effect of the initial tumor volume was assessed by comparing the efficacy of Bs20x22 administered before xenografts grew versus treatment of established tumors; significantly, greater efficacy was found when treatment was initiated before tumors could become established.


Subject(s)
Antibodies, Bispecific/immunology , Antibodies, Monoclonal/immunology , Antigens, CD20/immunology , Burkitt Lymphoma/therapy , Sialic Acid Binding Ig-like Lectin 2/immunology , Animals , Antibodies, Bispecific/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Murine-Derived/immunology , Antibodies, Monoclonal, Murine-Derived/pharmacology , Burkitt Lymphoma/immunology , Cell Line, Tumor , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Rituximab , Transfection , Xenograft Model Antitumor Assays
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