ABSTRACT
Bladder cancer is a frequent malignancy and has a clinical need for new therapeutic approaches. Antibody and protein technologies came a long way in recent years and new engineering approaches were applied to generate innovative therapeutic entities with novel mechanisms of action. Furthermore, mRNA-based pharmaceuticals recently reached the market and CAR-T cells and viral-based gene therapy remain a major focus of biomedical research. This review focuses on the engineering of biologics, particularly therapeutic antibodies and their application in preclinical development and clinical trials, as well as approved monoclonal antibodies for the treatment of bladder cancer. Besides, newly emerging entities in the realm of bladder cancer like mRNA, gene therapy or cell-based therapeutics are discussed and evaluated. As many discussed molecules exhibit unique mechanisms of action based on innovative protein engineering, they reflect the next generation of cancer drugs. This review will shed light on the engineering strategies applied to develop these next generation treatments and provides deeper insights into their preclinical profiles, clinical stages, and ongoing trials. Furthermore, the distribution and expression of the targeted antigens and the intended mechanisms of action are elucidated.
ABSTRACT
Combining different treatment strategies offers the possibility of improving treatment results for cancer patients. The aim of our study was therefore to investigate the combination of treatment of established s.c. human B non-Hodgkin's lymphoma in severe immune deficient mice using a recombinant bispecific CD19 x CD16 diabody (targeting natural killer cells to CD19 cells) and the angiogenesis inhibitor thalidomide. Monotherapy with either thalidomide or diabody caused an approximate 50% reduction in tumor growth rate. The combined treatment showed evidence for a synergistic effect resulting in a 74% reduction in median tumor size. In the combined treatment group, two of five animals had complete remissions of their s.c. tumor. These results suggest that a combination treatment with recombinant diabodies and angiogenesis inhibition represents a useful approach in cancer therapy.
Subject(s)
Antibodies, Bispecific/therapeutic use , Antigens, CD19/immunology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/pathology , Receptors, IgG/immunology , Thalidomide/pharmacology , Animals , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor/methods , Growth Inhibitors/pharmacology , Humans , Mice , Mice, Inbred BALB C , Mice, SCID , Recombinant Proteins/pharmacology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays/methodsABSTRACT
To target NK cells against non-Hodgkin's lymphoma, we constructed a bispecific diabody (BsDb) with reactivity against both human CD19 and FcgammaRIII (CD16). Bacterially produced CD19 x CD16 BsDb specifically interacted with both CD19(+) and CD16(+) cells and exhibited significantly higher apparent affinity and slower dissociation from the tumor cells than from effector cells. It was able to induce specific lysis of tumor cells in the presence of isolated human NK cells or nonfractionated PBLs. The combination of the CD19 x CD16 BsDb with a previously described CD19 x CD3 BsDb and CD28 costimulation significantly increased the lytic potential of human PBLs. Treatment of SCID mice bearing an established Burkitt's lymphoma (5 mm in diameter) with human PBLs, CD19 x CD16 BsDb, CD19 x CD3 BsDb, and anti-CD28 mAb resulted in the complete elimination of tumors in 80% of animals. In contrast, mice receiving human PBLs in combination with either diabody alone showed only partial tumor regression. These data clearly demonstrate the synergistic effect of small recombinant bispecific molecules recruiting different populations of human effector cells to the same tumor target.
Subject(s)
Antibodies, Bispecific/pharmacology , Antigens, CD19/immunology , Antineoplastic Agents/pharmacology , CD3 Complex/immunology , Drug Screening Assays, Antitumor/methods , Lymphoma, Non-Hodgkin/immunology , Lymphoma, Non-Hodgkin/therapy , Receptors, IgG/immunology , Animals , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/biosynthesis , Antibodies, Bispecific/genetics , Antibody Specificity/genetics , Antigens, CD19/genetics , Antigens, CD19/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemical synthesis , Binding Sites, Antibody/genetics , Biosensing Techniques , Burkitt Lymphoma/immunology , Burkitt Lymphoma/therapy , CD3 Complex/genetics , Cell Line , Cytotoxicity, Immunologic/genetics , Drug Synergism , Humans , Injections, Intravenous , Jurkat Cells , Killer Cells, Natural/immunology , Lymphoma, Non-Hodgkin/pathology , Mice , Mice, SCID , Receptors, IgG/genetics , Receptors, IgG/metabolism , Recombinant Proteins/administration & dosage , Recombinant Proteins/chemical synthesis , Recombinant Proteins/genetics , Recombinant Proteins/pharmacology , Tumor Cells, CulturedABSTRACT
ScOKT3-gammaDeltaIgM VAEVD is a recombinant chimeric anti-CD3 antibody variant consisting of the light and heavy variable binding domains of the OKT3 monoclonal antibody and the CH3 and CH4 domains of a human IgM mutation linked by a human IgG3 hinge region. Due to the IgM Fc domains, scOKT3-gammaDeltaIgM VAEVD antibodies are able to form polymeric structures. Independent of their polymerization state, they possess in vitro CD3 modulating and immunosuppressive properties while inducing only minimal T cell activation compared to their monoclonal counterpart. To evaluate the in vivo efficacy of the antibodies, an adjuvant-induced chronic inflammation was established in human CD3 transgenic mice. Administration of four doses of 15 microg of isolated scOKT3-gammaDeltaIgM VAEVD monomers and pentamers significantly reduced diameters of inflamed ankle joints in a manner comparable to the monoclonal antibody OKT3. Additionally, the antibody treatment lead to a significant reduction of the cytokine levels (IL-2, TNF-alpha and INF-gamma) in the mice's sera. These results suggest that scOKT3-gammaDeltaIgM VAEVD antibodies may provide a useful alternative to the OKT3 mAb for clinical immunosuppressive treatment for auto-aggressive diseases or for organ-transplantation.
