Non-Hodgkin lymphoma (NHL) represents a significant clinical challenge in cancer management. Approximately 70,000 new cases of NHL are diagnosed annually in the U.S. and NHL ranks fifth in cancer incidence and mortality. The majority of NHL cases are of B-cell origin and more than 90% express the leukocyte antigen CD20, making these cancers amenable to targeted therapeutic approaches. As a result, B-cell depletion therapies using the anti-CD20 antibody (Ab), rituximab, given alone or in combination with chemotherapy regimens, has been shown to significantly outcome of patients with a range of B-cell malignancies including NHL and chronic lymphocytic leukemia (CLL). However, relapse is a common occurrence in rituximab-treated patients and there remains a need for more durable first-line therapies and more effective options for patients with rituximab-refractory disease. We are using a proprietary protein scaffold comprising IL-15 and IL-15 receptor ¿ (IL-15R¿)/IgG Fc domains to create potent CD20-targeted immunotherapeutic agents. Specifically, we have generated a fusion protein complex (2B8T2M) with single- chain Ab domains derived from rituximab linked to both an IL-15 superagonist variant and an IL-15R¿/Fc fusion. High affinity interactions between the IL-15 and IL-15R¿ fusion proteins result in a stable soluble multivalent complex that retains functional binding activities of the anti-CD20 Ab, IL-15 and Fc components. The IL-15 domain of 2B8T2M is expected to provide potent antitumor immunostimulatory activity against B- lymphoma cells at the tumor site. IL-15 is a critical cytokine for the proliferation and activation of effector natural killer and T cells and plays a maor role in memory T cell maintenance. Based on its potential to elicit long-lasting immune responses, a recent NCI review listed IL-15 as the most promising immunotherapeutic candidate that could potentially cure cancer. The 2B8T2M complex was shown to be capable of directing complement dependent and antibody-dependent cellular cytotoxicity against human lymphoma cells with comparable activity to that seen with rituximab. Surprisingly, the 2B8T2M complex also exhibits higher levels of direct cell killing of human lymphomas than were observed with rituximab. Overall, the anti-lymphoma activity of the 2B8T2M complex exceeded that of the rituximab, suggesting that 2B8T2M is a superior therapeutic agent against CD20+ NHL. Based on these promising results, we intend under this proposal to further characterize efficacy of the CD20-targeted IL-15 fusion protein complexes in well-established B-cell lymphoma xenograft animal models. Additionally, the pharmacokinetic and toxicity profile of the 2B8T2M complex will be evaluated and an optimal treatment regimen against B-cell lymphomas will be developed. Positive results from these studies will allow advancement of 2B8T2M into preclinical efficacy and GLP toxicology studies and product process development/manufacture as part of an SBIR Phase II project. The overall goal is the submission of an IND to support clinical testing of 2B8T2M in patients with NHL and/or CLL.
Public Health Relevance: While anti-CD20 antibody therapy provides patients with B-cell malignancies with significant clinical benefit, indolent lymphomas, such as follicular lymphoma and chronic lymphocytic leukemia (CLL), remain incurable with patients exhibiting relapses and refractory disease, highlighting the need for more effective durable treatment options. Under this Phase I proposal, we intend to evaluate the preclinical efficacy and safety of a novel CD20-targeted immunotherapeutic complex that has the capacity to mediate antibody-directed cytotoxicity against B-cell lymphomas and provide potent, long-lasting IL-15-mediated immunostimulation to effector cells. Positive outcomes from the proposed animal studies would provide justification to advancement of this approach into additional non-clinical studies and product manufacture in preparation for clinical testing in patients with non-Hodgkin lymphomas and CLL.
Public Health Relevance Statement: While anti-CD20 antibody therapy provides patients with B-cell malignancies with significant clinical benefit, indolent lymphomas, such as follicular lymphoma and chronic lymphocytic leukemia (CLL), remain incurable with patients exhibiting relapses and refractory disease, highlighting the need for more effective durable treatment options. Under this Phase I proposal, we intend to evaluate the preclinical efficacy and safety of a novel CD20-targeted immunotherapeutic complex that has the capacity to mediate antibody-directed cytotoxicity against B-cell lymphomas and provide potent, long-lasting IL-15-mediated immunostimulation to effector cells. Positive outcomes from the proposed animal studies would provide justification to advancement of this approach into additional non-clinical studies and product manufacture in preparation for clinical testing in patients with non-Hodgkin lymphomas and CLL.
NIH Spending Category: Cancer; Hematology; Lymphoma; Orphan Drug; Rare Diseases
Project Terms: Address; Affinity; Animal Model; Animals; Antibodies; Antibody -dependent cell cytotoxicity; Antibody Therapy; Apoptosis; B lymphoid malignancy; B-Cell Lymphomas; B-Lymphocytes; base; Binding (Molecular Function); Bone Marrow; Burkitt Lymphoma; cell killing; Cell Maintenance; Cells; Chemotherapy-Oncologic Procedure; Chimeric Proteins; Chronic Lymphocytic Leukemia; Clinical; comparative; Complement; Complement-Dependent Cytotoxicity; Complex; cytokine; cytotoxicity; Data; design; Development; Diagnosis; disulfide bond; Dose; Drug Kinetics; Effector Cell; Evaluation; Exhibits; Fc domain; Fc Receptor; Follicular Lymphoma; Goals; HLA Antigens; Human; IgG Receptors; IgG1; Immune; Immune response; Immune Tolerance; Immunization; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; improved; Inbred BALB C Mice; Incidence; Indolent; Interleukin-15; interleukin-15 receptor; killer T cell; Link; Lymphoma; Malignant Neoplasms; manufacturing process development; Mediating; Memory; Mortality Vital Statistics; mouse model; MS4A1 gene; Mus; neoplastic cell; next generation; Non-Hodgkin's Lymphoma; novel; Outcome; Patients; Pharmaceutical Preparations; Phase; Play; preclinical efficacy; preclinical safety; Preparation; Progression-Free Survivals; protein complex; receptor; Refractory Disease; Relapse; Relative (related person); research clinical testing; Resistance; response; rituximab; Role; Safety; scaffold; Scaffolding Protein; Schedule; SCID Mice; Site; Small Business Innovation Research Grant; Testing; Therapeutic Agents; Therapeutic Effect; therapeutic target; tositumomab; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; tumor; Variant; Xenograft Model; Xenograft procedu
