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Generation of antibody-drug conjugates by proximity-based sortase-mediated ligation

Award Number: R44CA221374
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Generation of antibody-drug conjugates by proximity-based sortase-mediated ligation - There has been growing interest in the use of antibody drug conjugates (ADCs) for the treatment of cancer as mounting data suggests an increase in anti-tumor effectiveness and reduced toxicity, compared with the administration of unlabeled antibodies in combination with chemotherapy. Recent evidence has shown that differentially labeled antibodies, i.e. labeled at different locations and with different numbers, can have distinct therapeutic and pharmacokinetic properties and some subpopulations can show little, if any, therapeutic activity yet account for most of the toxicity. Therefore, there has been a movement towards the development of site- specific ADCs, which are precisely labeled with drugs at pre-defined locations. We have recently developed two new approaches for the preparation of highly uniform ADCs, one site-specific bioconjugation approach, Proximity-Based Sortase-mediated protein Ligation (PBS-PL), whereby sortase is used to ligate drugs to a peptide tag that has been introduced into the antibody backbone, and one region- specific bioconjugation approach, Proximity-based Sortase Isopeptide Ligation (PBS-IL), which allows for the labeling of native antibodies with reduced variability compared with current lysine/cysteine residue labeling approaches. Both methods produce ADCs in high yields, are compatible with glycosylated IgG, and offer unlimited flexibility in antibody-drug linker chemistry. Therefore, we believe that these technologies will provide new, favorable approaches for the production of ADCs that will be of interest to the pharmaceutical industry. In this proposal, we have partnered with Integral Molecular and the University of Pennsylvania to develop ADCs against claudin-18 (CLDN 18.2). CLD18.2 is ectopically expressed in several cancers including pancreatic cancer, which is the focus of this proposal. Outcomes for pancreatic cancer patients are poor with a 5-year survival of <8% due to a lack of effective treatment modalities. Therefore, the development of new therapies are a clinical necessity. The highly selective expression of CLDN18.2 in cancer, with no detectable expression on any healthy adult tissues that are accessible to antibodies, make it an attractive option for targeted therapy. We will prepare various ADCs using PBS-PL and PBS-IL and will identify the conjugation approach and ADC formulation that is expected to be most favorable for clinical translation, based on serum stability, pharmacokinetics, and efficacy. Pre-clinical testing will be performed in an orthotopic pancreatic tumor model in syngeneic mice. The specific aims for the proposal are: Aim 1: Produce and characterize anti- CLDN18.2-vcMMAE ADCs using PBS-PL and PBS-IL; Aim 2: Evaluate the binding and efficacy of anti- CLDN18.2-vcMMAE ADCs in vitro; Aim 3. Determine the pharmacokinetics and efficacy of anti-CLDN18.2 ADCs in a murine tumor model


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: 2025 ( Subtotal = $0 )
2025	2022	ALPHATHERA, INC.	19 STONE CREEK LN	BRYN MAWR	PA	19010	DELAWARE	USA	Cancer Treatment Research	000	3	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $610,986 )
2022	2022	ALPHATHERA	19 STONE CREEK LN	BRYN MAWR	PA	19010	DELAWARE	USA	Cancer Treatment Research	000	3	6/9/2022	NON-COMPETING CONTINUATION	$610,986
														Subtotal = $610,986

Issue Date FY: 2021 ( Subtotal = $1,081,188 )
2021	2021	ALPHATHERA	19 STONE CREEK LN	BRYN MAWR	PA	19010	DELAWARE	USA	Cancer Treatment Research	000	2	6/24/2021	COMPETING CONTINUATION	$1,081,188
														Subtotal = $1,081,188

Grand Total All Awards = $1,692,174

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Generation of antibody-drug conjugates by proximity-based sortase-mediated ligation

Award Number: R44CA221374

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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