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Development of Anti-EGFR-huEndo-P125A: A combined Vasculogenic Mimicry-Angiogenesis inhibitory therapeutic for Triple Negative Breast Cancer

Award Number: R44CA265690
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 03/27/2023

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Development of Anti-EGFR-huEndo-P125A: A combined Vasculogenic Mimicry-Angiogenesis inhibitory therapeutic for Triple Negative Breast Cancer - PROJECT SUMMARY/ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive breast cancer (BC) subtype which comprises approximately 20% of newly diagnosed BCs. Although epidermal growth factor receptor (EGFR) is expressed in ~60% of TNBC and 65-72% of basal-like BCs, the anti-EGFR MAb, Cetuximab (Erbitux®), elicits little response as a single-agent or when combined with chemotherapy. Aggressive metastatic behavior of TNBC correlates with the ability to form vascular channels lined by tumor cells themselves, known as Vasculogenic Mimicry (VM), and the formation of cellular protrusions called ‘invadopodia’ that facilitate cellular migration, intravasation and metastasis. Although angiogenesis plays a central role in BC growth and metastasis, combined therapeutic targeting of angiogenesis and VM has largely been untested. We have synthesized an antibody-fusion protein, aEGFR-huEndo-P125A (EEPA125) by linking the heavy chains of an anti-EGFR IgG1 with a highly anti- angiogenic “payload”, huEndoP125A, which is a P125 --> A125 mutant of human endostatin. EEPA125 inhibited both angiogenesis, and VM, which was not seen with cetuximab nor huEndo-P125A alone. A combination of anti-EGFR IgG1 and huEndo-P125A in non-fused form did not inhibit VM suggesting that the delivery of dimeric huEndo-P125A by EEPA125 fusion is essential for VM inhibition. We successfully produced and purified EEPA125 from a stable pool of CHO cells to >95% purity. Testing of EEPA125 in vivo showed inhibition of MDA-MB-468 TNBC tumor growth and metastatic spread than cetuximab. EEPA125 more effective also markedly reduced lung metastasis following intravenous administration of lung tropic MDA-MB-231-4175 TNBC cells, and improved survival of mice compared to cetuximab treatment. EEPA125 also demonstrated ADCC activity, and it markedly inhibited Wnt/b-catenin signaling, TNBC motility and migration, and invadopodia formation. Furthermore, it reduced the secretion of soluble MMP2 and MT1-MMP proteins by TNBC cells compared to treatment with huEndo-P125A, or cetuximab. We also characterized the serum elimination pattern of EEPA125 in immunocompromised mice. We now propose to carry out confirmatory in vivo efficacy testing of EEPA125 using clinically relevant TNBC PDX (patient derived xenograft) models, and to study EEPA125 efficacy in preventing increased VM and “rebound angiogenesis” induced following treatment with the anti-angiogenic VEGFR inhibitor sunitinib. Combination with chemotherapeutic agents such as paclitaxel with EEPA125 will be tested. We will generate a stable CHO cell clone for process engineering and cGMP manufacture of EEPA125, and perform PK/PD and toxicology/safety studies in immunocompromised and immunocompetent rodents and in cynomolgus monkeys. We will also develop an EGFR expressing murine breast cancer model and investigate the immune effects of EEPA125 when combined with of an anti PD-L1 checkpoint inhibitor in immunocompetent mice. Results generated will enable a risk-benefit assessment in preparation for a pre-IND meeting with the FDA and the eventual filing of an IND for Phase I/II testing.


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: 2024 ( Subtotal = -$400,000 )
2024	2022	SYNERGYS BIOTHERAPEUTICS INC	3189 DANVILLE BLVD	ALAMO	CA	94507	CONTRA COSTA	USA	Cancer Treatment Research	000	1	4/9/2024	NEW	-$400,000
														Subtotal = -$400,000

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	SYNERGYS BIOTHERAPEUTICS INC	3189 DANVILLE BLVD	ALAMO	CA	94507	CONTRA COSTA	USA	Cancer Treatment Research	001	1	3/29/2023	NEW	$0
2023	2022	SYNERGYS BIOTHERAPEUTICS INC	3189 DANVILLE BLVD	ALAMO	CA	94507	CONTRA COSTA	USA	Cancer Treatment Research	000	1	10/28/2022	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $400,000 )
2022	2022	SYNERGYS BIOTHERAPEUTICS, INC.	3189 DANVILLE BLVD STE 295	ALAMO	CA	94507	CONTRA COSTA	USA	Cancer Treatment Research	000	1	9/20/2022	NEW	$400,000
														Subtotal = $400,000

Grand Total All Awards = $0

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Development of Anti-EGFR-huEndo-P125A: A combined Vasculogenic Mimicry-Angiogenesis inhibitory therapeutic for Triple Negative Breast Cancer

Award Number: R44CA265690

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 03/27/2023

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