Alternative therapies for drug refractory B cell malignancies are urgently needed. We used advances last cycle to develop a new class of recombinant bispecific targeted toxin with expanded ability to recognize a wider range of B cell cancers. With funding from this grant, we discovered that bispecific targeted toxins could be made by fusing two repeating scFv subunits creating a bispecific ligand directed toxin and they had superior activity over monospecific targeted toxins. We brought the drug to clinical trial for leukemia. Findings are encouraging, but preliminary data indicates that toxin immunogenicity will be a problem as anticipated. Multiple dosing is required to obtain sustained remissions and this generates anti-toxin antibodies that impact drug efficacy. To this end, we have found an important new and successful way to deimmunize our toxin that may have implications for deimmunizing other molecules.
In aim 1, we propose to study this deimmunization. Funding from this proposal has also led to the development of a very different targeted toxin that has the ability to target cancer stem cells. Current theory dictates that cancer cells differentiate as do normal cells. The cancer cell population consists of a small cohort of less differentiated, self renewing, tumor initiating stem cells and a larger cohort of more differentiated tumor cells. More differentiated cells are more susceptible to chemotherapy and the minor fraction of less differentiated cancer stem cells are more drug resistant, thus contributing to drug refractory relapse in cancer. We have created a new targeted toxin that targets cancer stem cells and clearly has therapeutic efficacy in systemic mouse models of cancer. The agent has the advantage of working against a variety of different cancers.
In aim 2, we propose to study this new strategy of targeting tumor stem cells.
Aim 1 relates to Aim 2 since the deimmunization strategies are used to construct anti-stem cell targeted toxins as well.
Our group has discovered a new class of biological drugs called bispecific targeted toxins that show superiority over their monospecific counterparts and can be genetically modified to address some of the major problems in the field and we have proven that multiple treatments with these drugs are highly effective against systemic cancer in animals resulting in long-term disease free survivors. In this proposal, we will be addressing some of the major issues with these drugs. We will be investigating improvements in reducing their immunogenicity and destroying the most important drug resistant cells, cancer stem cells.
|Vallera, Daniel A; Felices, Martin; McElmurry, Ron et al. (2016) IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function. Clin Cancer Res 22:3440-50|
|Schmohl, J U; Gleason, M K; Dougherty, P R et al. (2016) Heterodimeric Bispecific Single Chain Variable Fragments (scFv) Killer Engagers (BiKEs) Enhance NK-cell Activity Against CD133+ Colorectal Cancer Cells. Target Oncol 11:353-61|
|Schmohl, Joerg U; Felices, Martin; Taras, Elizabeth et al. (2016) Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker. Mol Ther 24:1312-22|
|Bachanova, Veronika; Frankel, Arthur E; Cao, Qing et al. (2015) Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies. Clin Cancer Res 21:1267-72|
|Schmohl, Joerg U; Todhunter, Deborah; Oh, Seung et al. (2015) Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development. Toxins (Basel) 7:4067-82|
|Gleason, Michelle K; Ross, Julie A; Warlick, Erica D et al. (2014) CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123:3016-26|
|Waldron, Nate N; Barsky, Sanford H; Dougherty, Phillip R et al. (2014) A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma. Target Oncol 9:239-49|
|Schappa, Jill T; Frantz, Aric M; Gorden, Brandi H et al. (2013) Hemangiosarcoma and its cancer stem cell subpopulation are effectively killed by a toxin targeted through epidermal growth factor and urokinase receptors. Int J Cancer 133:1936-44|
|Wiernik, Andres; Foley, Bree; Zhang, Bin et al. (2013) Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition. Clin Cancer Res 19:3844-55|
|Skubitz, Amy P N; Taras, Elizabeth P; Boylan, Kristin L M et al. (2013) Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecol Oncol 130:579-87|
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