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DEFINING THE ROLE OF AFFINITY IN ANTIBODY-BASED TUMOR TARGETING AND PENETRATION

Award Number: R01CA118159
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/05/2007
PERIOD OF PERFORMANCE END DATE: 12/31/2013

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DEFINING THE ROLE OF AFFINITY IN ANTIBODY-BASED TUMOR TARGETING AND PENETRATION - Due to their recent demonstration of efficacy in a number of malignancies, monoclonal antibodies (MAb) are becoming increasingly important in cancer therapy. Most efforts to develop new antibody-based molecules are focused on identifying those with the highest possible affinity for the tumor antigen. Using small, single- chain Fv (scFv) molecules that ranged in affinity for the same epitope of HER2 from 1x10-7 M to 1x10-11 M. We showed that high affinity may impair the ability of an antibody to penetrate into a solid tumor, leading to perivascular localization and potential suboptimal therapeutic efficacy. This work validated a "Binding Site Barrier" hypothesis posed by Weinstein that stated that antibodies of very high affinity would be limited in their ability to penetrate solid tumors. A limitation of our earlier work was that scFv are rapidly eliminated from the circulation, thus limiting the ability to study tumor penetration over time. We have recently generated full-length IgG versions of the scFv molecules described above and are in the position to elucidate the role of affinity in tumor targeting and penetration and determine the mechanisms underlying this process. Preliminary data indicate that high affinity also detracts from tumor targeting and penetration of Ig. The hypotheses underlying this proposal are that 1) IgG molecules with very high affinity for tumor antigen will demonstrate a reduced ability to penetrate into solid tumors, 2) a major mechanism behind the restricted penetration of high affinity antibodies into solid tumors is the internalization and degradation by tumor cells and 3) lower affinity IgG molecules may be superior to higher affinity antibodies in mediating anti-tumor effects. We will evaluate the roles of binding affinity, antigen shedding, antigen/MAb internalization and normal tissue antigen expression on the tumor targeting and tumor penetration of anti-HER2 MAbs. We will also determine if changes in affinity, and the attendant impacts on tumor targeting and penetration, influence the anti-tumor efficacy of unconjugated anti-tumor MAbs, thereby providing information that can help guide future rational development of anti-tumor MAbs. This research is directly relevant to public health, as it will guide the development of new antibodies for the treatment of cancer. Learning how the binding strength (affinity) of an antibody for its target on the tumor cell surface affects the ability of the antibody to move into the tumor and kill tumor cells will allow us to create more effective antibody-based treatments for cancer.


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 = $0 )
2013	2011	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	000	5	12/28/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2011 ( Subtotal = $305,975 )
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	001	5	5/13/2011	NON-COMPETING CONTINUATION	$22,080
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	000	5	12/10/2010	NON-COMPETING CONTINUATION	$283,895
														Subtotal = $305,975

Issue Date FY: 2010 ( Subtotal = $315,438 )
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	000	4	1/14/2010	NON-COMPETING CONTINUATION	$311,607
2010	2010	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	001	4	1/21/2010	NON-COMPETING CONTINUATION	$3,831
														Subtotal = $315,438

Issue Date FY: 2009 ( Subtotal = $311,607 )
2009	2009	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	000	3	1/14/2009	NON-COMPETING CONTINUATION	$280,447
2009	2009	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	001	3	3/20/2009	NON-COMPETING CONTINUATION	$31,160
														Subtotal = $311,607

Issue Date FY: 2008 ( Subtotal = $311,607 )
2008	2008	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	000	2	1/3/2008	NON-COMPETING CONTINUATION	$311,607
														Subtotal = $311,607

Issue Date FY: 2007 ( Subtotal = $311,036 )
2007	2007	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Treatment Research	000	1	2/5/2007	NEW	$311,036
														Subtotal = $311,036

Grand Total All Awards = $1,555,663

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DEFINING THE ROLE OF AFFINITY IN ANTIBODY-BASED TUMOR TARGETING AND PENETRATION

Award Number: R01CA118159

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/05/2007

PERIOD OF PERFORMANCE END DATE: 12/31/2013

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