SBIR-STTR Award

Optimizing Therapeutic Index Of Mab-Ifn_alpha Molecule To Treat Lymphoma
Award last edited on: 9/20/13

Sponsored Program
SBIR
Awarding Agency
NIH : NCI
Total Award Amount
$201,213
Award Phase
1
Solicitation Topic Code
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Principal Investigator
N/A

Company Information

Immungene Inc

558 Street Charles Drive Suite 200
Thousand Oaks, CA 91360
   (805) 496-6700
   bd@immungene.com
   www.immungene.com
Location: Single
Congr. District: 26
County: Ventura

Phase I

Contract Number: 1R43CA162762-01A1
Start Date: 8/14/12    Completed: 2/13/13
Phase I year
2012
Phase I Amount
$201,213
This proposal is designed to optimize the monoclonal antibody-IFN¿ fusion molecule (mAb-IFN) by introducing several point mutations in the IFN¿ part of the molecule. Recently, we discovered that mAb- IFN¿ fusion molecule is about 4 log units more potent at activating the type 1 IFN receptor (IFNAR) on cells which express the antibody target protein than it is at stimulating IFNAR on cells which do not express the antibody target protein. The mAb-IFN¿ fusion molecule is about 2 log units less potent compared to non- fused IFN¿ on cells which do not express the antibody target protein, and about 2 log units more potent than non-fused IFN¿ at activating the IFNAR on cells which express the antibody target protein. The decrease in intrinsic potency of the mAb-IFN¿ fusion molecule is likely due to steric hindrance, and the increase in activity on cells which express the target of the antibody is likely due to the antibody localizing the fused IFN¿ to the cell surface, so that little or none ofthe intrinsic binding energy of IFN¿ for its receptor has to be used to pay the cost of entropy loss incurred when the bound IFN¿ is localized on the cell surface. Thus, the "effective concentration" of the fused IFN¿ is much higher than its actual concentration. Thus, a way has been discovered to considerably increase the therapeutic index of IFN¿ for treatment of cancer by fusing IFN¿ to antibodies which bind selectively to cancer cells, since the antiproliferative an proapoptotic effects of IFN¿ on cancer cells are desired for the therapeutic benefit, while stimulation of the receptor on non cancer cells causes the dose-limiting adverse effects of IFN¿. We and our collaborators at the UCLA will explore the effect of varying the intrinsic affinity of IFN¿ for its receptor by introducing a series of mutations into IFN¿ part of the fusion protein, then determining the effects of changes in affinity of IFN¿ for its receptor on the potency difference of the fusion protein between stimulating IFNAR on cells which express the antibody target protein and those which do not. Based on the rationale provided above for the increase in potency of the fusion protein on cells which express the antibody target protein, in spite of a decrease in intrinsic potency of the fused IFN¿, we expect that further decreasing the intrinsic potency of the IFN¿ in the fusion protein will further increase the potency difference between cells which do and do not express the target protein of the antibody, with the result of further increasing the therapeutic index of the fusion protein. We will test this prediction, and use our findings to drive selection of specific fusion molecules for development as cancer therapeutics. This proposal specifically focuses to optimize anti-CD20-IFN¿ fusion molecule to treat human B cell malignancies.

Public Health Relevance:
IFN¿ has potent anti-tumor activities; however its usage in the clinic has been restricted due to dose limiting toxicity. Monoclonal antibodies-IFN¿ (mAb-IFN) fusion molecules, developed by ImmunGene, have demonstrated efficacy and safety in animal models of cancer which are resistant to the treatment with either the antibody alone, IFN¿ alone, and to both in combination. Based on these data, we believe that mAb-IFN fusion molecules can be an effective treatment for a significant number of patients who do not respond to current cancer therapeutics. We propose to optimize the IFN part of the mAb-IFN fusion molecule to further increase the therapeutic index. An optimized therapeutic will overcome several limitations of existing targeted therapeutics, e.g. genetic (Fc?R polymorphism) and acquired drug resistance, lower dose - patients' convenience and cost effective.

Public Health Relevance Statement:
IFN¿ has potent anti-tumor activities; however its usage in the clinic has been restricted due to dose limiting toxicity. Monoclonal antibodies-IFN¿ (mAb-IFN) fusion molecules, developed by ImmunGene, have demonstrated efficacy and safety in animal models of cancer which are resistant to the treatment with either the antibody alone, IFN¿ alone, and to both in combination. Based on these data, we believe that mAb-IFN fusion molecules can be an effective treatment for a significant number of patients who do not respond to current cancer therapeutics. We propose to optimize the IFN part of the mAb-IFN fusion molecule to further increase the therapeutic index. An optimized therapeutic will overcome several limitations of existing targeted therapeutics, e.g. genetic (Fc?R polymorphism) and acquired drug resistance, lower dose - patients' convenience and cost effective.

NIH Spending Category:
Biotechnology; Cancer; Hematology; Lymphoma; Rare Diseases

Project Terms:
Adverse effects; Affect; Affinity; Animal Cancer Model; Antibodies; Antigen Targeting; Apoptotic; Avidity; B lymphoid malignancy; base; Binding (Molecular Function); cancer cell; Cancer Model; Cancer Patient; cancer therapy; cell killing; Cell Line; Cell surface; Cells; Chimeric Proteins; Clinic; Complex; cost; cost effective; Data; design; Development; Dissociation; Dose; Dose-Limiting; Drug resistance; effective therapy; Engineering; Entropy; Equilibrium; flexibility; follow-up; Genetic; Genetic Polymorphism; Growth; Human; IFNAR1 gene; IFNAR2 gene; Interferons; Killings; Kinetics; knowledge base; Lymphoma; Malignant Neoplasms; Modeling; Monoclonal Antibodies; MS4A1 gene; mutant; Mutation; Patients; Phage Display; Point Mutation; Property; Proteins; Publishing; receptor; Research; Resistance; Safety; Series; Structure; System; Testing; Therapeutic; Therapeutic Index; therapeutic target; Toxic ef

Phase II

Contract Number: ----------
Start Date: 00/00/00    Completed: 00/00/00
Phase II year
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Phase II Amount
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