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Bacon, Francis

Banerjee, Pubali

Baviello, George

Bhatia,, Hema

Dolan, Michael

Izumida, Kyo

Kim, Skaison

Lowe, Christopher

Miao, Judy

Oppenheim, Sheldon

Tchoudakova, Anna

English

Engineering Conferences International

Poster Number 123 CHALLENGES WE JUST COULDN’T IgG-NORE: CASE STUDIES OF PROCESS OPTIMIZATION FOR NEXT-GENERATION, HIGHLY ENGINEERED MULTISPECIFICS  Michael Dolan, Takeda michael.dolan@takeda.com Hema Bhatia, Takeda  Christopher Lowe, Takeda Francis Bacon, Takeda Pubali Banerjee, Takeda  George Baviello, Takeda Anna Tchoudakova, Takeda Skaison Kim, Takeda Judy Miao, Takeda  Kyo Izumida, Takeda Sheldon Oppenheim,Takeda   Despite clinical successes of some bispecific antibodies in treating liquid cancers, efficacy toward solid tumors remains a significant hurdle. The high potency of many T-cell-directed bispecific antibodies and their lack of discernment between tumor cells and healthy tissues means that even very low expression levels of target cell surface antigens by healthy tissues can result in safety risks for patients. As a consequence, dose levels of these compounds are restricted, limiting their therapeutic potential.  Highly-engineered, multispecific proteins have begun emerging from drug discovery efforts as potential solutions to some of the aforementioned challenges. This work will explore several approaches undertaken across both cell line development and cell culture development at Takeda to overcome hurdles on the path to develop and manufacture such potential therapeutics. While several approaches have yielded success, others are more limited in their impact. Some of the hurdles and approaches to solutions may include:  1. Development and examination of multiple production cell lines (one HEK and multiple CHO) to address low expression levels. 2. Investigation into lactate accumulation observed in the production bioreactor and implementation of a trace metal supplement to achieve the desired lactate metabolic shift, ensuring robust cell culture performance. 3. Resolution of high degrees of sequence heterogeneity and product cleavage by increasing the concentration of a component in a feed. 4. Analysis of spent culture medium to determine exhausted components (and supplement for increased productivity). 5. Screening of feed media. 6. Addition of antioxidants to reduce oxidative cellular stress.  Moreover, in order to meet desired limits for certain product quality attributes, additional solutions were implemented at the purification stage to remedy challenges that could not be fully resolved through cell culture optimization alone. Overall, this work will highlight the challenges and creative problem solving required in tackling proteins with such complex molecular architectures and biophysical properties.    

Challenges we just couldn’t IgG-nore: Case studies of process optimization for next- generation, highly engineered multispecifics

https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1170&context=ccexviii&type=additional

Challenges we just couldn’t IgG-nore: Case studies of process optimization for next- generation, highly engineered multispecifics

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Engineering Conferences International