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DIVERSIFYING MICA TO CREATE TARGETED ADAPTERS TO RECRUIT AND ACTIVATE NK CELLS TO

Award Number: R43TR001011
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2013
PERIOD OF PERFORMANCE END DATE: 09/14/2014

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DIVERSIFYING MICA TO CREATE TARGETED ADAPTERS TO RECRUIT AND ACTIVATE NK CELLS TO - DESCRIPTION (provided by applicant): Monoclonal antibodies targeting tumor associated antigens (TAA's) have since 1997, provided safe and efficacious human cancer therapeutics. More recently, bispecific antibodies or bispecific antibody fragments that promote immunologic synapses between cells of the innate immune system and malignant cells have shown in clinical trials remarkable efficacy and potency against several leukemias and lymphomas. We propose in this Phase I SBIR study to determine whether it is feasible to develop a platform based on engineering a novel human scaffold, MICA, to target and promote killing of specific cancer cells by generating specific immunologic synapses. NK cells and certain T-cells of the innate immune system protect the host from the malignant enemy within by constant surveillance for cells expressing surface MICA or MICB, indicators that the cell is a threat to the health of the host. Once such effector cells of the innate immunity detect a cell decorated by a membrane-bound MIC protein, they attack and destroy the decorated, threatening cell. Such threats include malignancies; but many cancerous cells do not express a level of MICA sufficient to recruit the effector cells. Many high grade malignant cells trap MIC protein intracellularly or secrete proteases that cleave the MIC protein from their surface, clearing the distress signal and enabling escape from innate immunity. Thus, in spite of being dangerous and threatening host survival, cancer cells can break through the surveillance by manipulating surface expression of MIC proteins. We propose to overcome this escape of malignant cells by decorating their surfaces with MICA from outside. Soluble MICA targeted specifically to TAA's expressed uniquely on the malignant cell surface would be administered parenterally. Such a novel approach enables an adaptive use of Nature's potent innate immunity to override the evolved, nefarious mechanism of cancer escape---"innate immunotherapy". The innovation lies in the conversion of this human MICA scaffold naturally deployed by the innate immune system into an immune "adaptor" that specifically binds malignant cells and thereby recruits and activates innate immunity effector cells expressing the receptor for MICA, NKG2D, to promptly kill the targeted cell. We propose herein to focus these platform technologies and concepts on a prototypic and important TAA, Fibroblast Growth Factor Receptor-3 (FGFR3), an oncogenic protein over expressed on most human bladder cancers and many multiple myeloma cells. We intend to demonstrate in vitro specific killing of human cells expressing FGFR3.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2013 ( Subtotal = $316,078 )
2013	2013	AVIDBIOTICS CORPORATION	230 EAST GRAND AVENUE	SOUTH SAN FRANCISCO	CA	94080	SAN MATEO	USA	National Center for Advancing Translational Sciences	000	1	9/10/2013	NEW	$316,078
														Subtotal = $316,078

Grand Total All Awards = $316,078

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DIVERSIFYING MICA TO CREATE TARGETED ADAPTERS TO RECRUIT AND ACTIVATE NK CELLS TO

Award Number: R43TR001011

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2013

PERIOD OF PERFORMANCE END DATE: 09/14/2014

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