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Optimizing Antibody Production in CHO Cells Using Epi-MAX Technology to Increase Heavy and Light Chain Expression

Award Number: R41TR005122
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: 04/15/2024
PERIOD OF PERFORMANCE END DATE: 04/14/2026

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Optimizing Antibody Production in CHO Cells Using Epi-MAX Technology to Increase Heavy and Light Chain Expression - ABSTRACT Codomax has developed the Epi-MAX platform, an integrated mass spectrometry omics and computational technology for enhanced protein synthesis. Current protein manufacturing processes typically employ expression vectors inserted into heterologous host cells, where gene, regulatory and cell features limit protein production; some proteins are difficult to express in high yields due to inefficiently translated or sub-optimally transcribed mRNA. Codomax's innovation hinges on the discovery that cells regulate translation in response to stress by altering the tRNA pools to enhance translation of mRNAs with distinct codon usage patterns. The Epi- MAX platform has leveraged this tRNA codon-based mechanism to increase recombinant protein expression in cells by matching codon usage in the target gene to the stress-reprogrammed tRNAs. Previously, Codomax demonstrated stress-induced tRNA reprogramming in mammalian systems and propose to extend the platform to antibody production in Chinese hamster ovary (CHO) cells. Underlying antibody production in CHO cells is the stress of high protein expression, evidenced by Codomax's observed changes in the levels of mRNAs and proteins specific to stress response, protein folding and metabolic genes when comparing high to low expressing clones. High antibody expression reprograms protein expression machinery with dramatic changes in ribosome components and translation factors. Codomax has shown that available levels of the CREB1 transcription factor, which drives target antibody expression, decrease in high expressing clones. Thus, the specific aims for Codomax's project include application of the Epi-MAX platform to analyze high and low productivity CHO clones for the model therapeutic antibody to identify tRNA systems that limit heavy chain production, and then identify tRNAs that when over-expressed, boost antibody expression (Aim 1). Codomax will then increase target heavy and light chain mRNA transcription 200%, by re-engineering the CMV-regulating CREB1 transcription factor to have increased stress-induced translation (Aim 2). Codon optimized CREB1 will be used to enhance mRNA translation during the stress of antibody expression, with maximized CREB1 transcription factor levels driving increased mRNA transcription from the CMV promoter. The CREB1 gene will be re-engineered using Epi-MAX data from Aim 1. Then CRISPR-Cas9 approaches will be used to replace the native CREB1 gene with the CREB1-codon optimized sequence and mRNA expression will be evaluated for the heavy and light chains under high expression conditions. Aim 2 will result in the generation of gene sequences, plasmids and CRISPR reagents for CMV-based transcription in several CHO lines. The successful completion of Codomax's Phase I project will demonstrate proof-of-concept that the Epi-MAX platform can be used to increase antibody yield from CHO cells and generate designer reagents that promote boosted antibody production.


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: 2026 ( Subtotal = $0 )
2026	2024	CODOMAX INC.	17 BRIDEN ST STE 220	WORCESTER	MA	01605	WORCESTER	USA	National Center for Advancing Translational Sciences	000	1	3/11/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $350,000 )
2024	2024	CODOMAX INC.	17 BRIDEN ST STE 219	WORCESTER	MA	01605	WORCESTER	USA	National Center for Advancing Translational Sciences	000	1	4/15/2024	NEW	$350,000
														Subtotal = $350,000

Grand Total All Awards = $350,000

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Optimizing Antibody Production in CHO Cells Using Epi-MAX Technology to Increase Heavy and Light Chain Expression

Award Number: R41TR005122

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: 04/15/2024

PERIOD OF PERFORMANCE END DATE: 04/14/2026

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