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Cambridge Healthtech Institute’s Inaugural
CMC Strategies for Antibody-Drug Conjugates
Strategies for Overcoming Developability and Manufacturability of ADCs
Part of CHI's 6th Annual The Bioprocessing Summit

August 18-19, 2014 | Renaissance Waterfront Hotel | Boston, Massachusetts


Day 1 | Day 2 | Short Courses | Download Brochure | Speaker Bios 

Tuesday, August 19

7:00 am Registration and Morning Coffee


ANALYTICAL CHARACTERIZATION
AND FORMULATION

7:55 Chairperson’s Remarks

Christian Schöneich, Ph.D., Takeru Higuchi Distinguished Professor and Chair, Pharmaceutical Chemistry, University of Kansas

8:00 The Heterogeneity of ADCs and Its Impact on Analytical Method Development and Characterization

Lily LiuLily Liu, BS, Principal Associate, Formulation and Analytical Development, Agensys, Inc.

The possible combinations of payloads and IgG isotypes confer additional heterogeneity to the ADC molecules, adding an extra layer of complexity over their mAb counterparts. This presentation will focus on challenges with regards to analytical methods and our approach to develop fit-for-purpose methods for release and stability testing to support IND filings. Characterization of the methods and the inferences to the structure of the ADCs will also be discussed.

8:30 Photodegradation Reactions of Antibodies and Antibody-Drug Conjugates

Christian SchöneichChristian Schöneich, Ph.D., Takeru Higuchi Distinguished Professor and Chair, Pharmaceutical Chemistry, University of Kansas

Chemical and physical stability problems of ADCs may arise from the exposure of ADCs to light, as (i) several ADCs contain drug conjugates, which may act as photosensitizer (e.g., CBI, duocarmycin or an anthraquinone moiety), and/or (ii) the conjugation of drug moieties to antibodies may change the sensitivity towards light exposure. This talk will focus on light-induced photodegradation of ADC mimics, designed to evaluate the light-sensitivity and degradation mechanisms of ADCs.

 

9:00 Characterization of Conformational Stability of Antibody-Drug Conjugates

Prasanta Patel, Ph.D., Principal Scientist, Progenics Pharmaceuticals, Inc.

Conformational stability of an antibody-drug conjugate relies on the structural integrity of the molecule. Elucidation of conformational aspects of the antibody is complex therefore orthogonal methods are frequently applied. Conformational stability of an antibody with a cytotoxic payload may alter the binding properties and potency of the conjugated antibody. An overview of various analytical methods for characterization of conformational stability of the antibody-drug conjugate will be presented.

9:30 Sponsored Presentation (Opportunity Available)

9:45 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 The Role of High Drug Payload on Physical Instability of Antibody-Drug Conjugates

Yilma Adem, MSc., Formulation Scientist, Pharmaceutical Development, Genentech, Inc.

The conjugation of hydrophobic cytotoxic agents such as monomethyl auristatin E (MMAE) to the interchain sulfhydryl groups of monoclonal antibodies (Mabs) through a protease-labile linker generates a heterogeneous drug load distribution. The conjugation process can generate high-drug-load species that can affect the physical stability of antibody−drug conjugates (ADCs). In this study, the mechanism of physical instability of ADCs was investigated by formulating the ADC pool as well as isolated drug load species in high and low ionic strength buffers to understand the effect of ionic strength on the stability of drug-conjugated Mabs. The results showed that the presence of high ionic strength buffer led to time-dependent aggregate and fragment formation of ADCs, predominantly ADCs with high-drug-load species under stress conditions. In addition, differential scanning calorimetry (DSC) results confirmed that there is a direct correlation between thermal unfolding and drug payload and that specific changes in the DSC thermogram profiles can be assigned to modifications by MMAE.

11:00 CQA-Based Approaches to Formulation Development of an ADC Program

Aditya WakankarAditya Wakankar, Ph.D., Associate Director, Formulation & Analytical Development, Stem CentRx LLC.

Knowledge of CQA for ADCs is being incorporated into the design of safe, efficacious and stable ADC drug product formulations. Quality attributes for an ADC can be categorized into those that are associated with the antibody-drug conjugate, the drug itself and those that are inherited from the antibody intermediate. This talk will provide perspective on what attributes are critical for an ADC (e.g. DAR, free drug) and how this information can be utilized to make informed formulation plans and decisions.

11:30 Development and Comparative Stability of Liquid and Lyophilized Formulations for a Developmental Maytansinoid ADC

Karan ShahKaran Shah, MSc., Analytical Associate III, Analytical and Pharmaceutical Sciences, Immunogen, Inc.

This presentation will discuss the screening studies that were performed to develop viable liquid and lypophilized formulation candidates for a development stage maytansinoid ADC.  The stability of the candidate formulations will be compared using a variety of analytical methods including SE-HPLC, RP-HPLC and reduced/non-reduced CE SDS. Important differences in the requirements for developing liquid and lyophilized formulations will also be discussed.

12:00 pm Enjoy Lunch on Your Own

1:15 Session Break


CMC, PROCESS DEVELOPMENT AND REGULATORY CONSIDERATIONS

1:55 Chairperson’s Remarks

Ian Schwartz, MSc., Senior Engineer, Process Development, Agensys, Inc.

2:00 Regulatory CMC Considerations for ADC Clinical Development

Mark TardieMark Tardie, MSc., Senior Regulatory Manager, Global Biotherapeutics CMC, Pfizer, Inc.

The significant number of antibody-drug conjugates (ADCs) currently in development is testament to their promising therapeutic benefit. In addition to the complexity of unconjugated monoclonal antibodies, ADCs exhibit unique properties, derived from the linkage of a biologically produced antibody to a small molecule drug, which require careful CMC consideration. This presentation will explore ADC development challenges, including the current lack of comprehensive specific regulatory guidance, the use of highly potent cytotoxic agents and the need for heightened analytical testing.

2:30 Process Development of Scalable Antibody-Drug Conjugate Manufacturing Processes: Points to Consider and Parameters to Control

Ian SchwartzIan Schwartz, MSc., Senior Engineer, Process Development, Agensys, Inc.

Antibody-Drug Conjugates (ADCs) are an exciting class of targeted therapies for the treatment of cancer. ADCs have process development and manufacturing challenges in part due to the uniqueness of combining a tumor targeting antibody with a potent small molecule cytotoxic agent. This presentation gives strategies for process development of scalable and robust ADC manufacturing processes.

3:00 Challenges and Considerations for Clinical Development and Manufacturing of ADCs

Steven MaxSteven Max, Ph.D., Associate Research Fellow, Biotherapeutics Pharmaceutical Sciences, Pfizer, Inc.

The increased interest in antibody-drug conjugates (ADCs) is a testament to their potential therapeutic and safety advantages over conventional chemotherapies. The ADC toolbox enables, for example, the ability to evaluate different linker-payload combinations, drug load (DAR) and conjugation chemistries in order to optimize stability, safety and efficacy in the clinic. However, these same options can provide CMC-specific challenges en route to regulatory approval and clinical dosing. This talk will address some key considerations during the development and manufacturing of ADCs.

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Externalization of ADC Manufacturing: Challenges and Triumphs

Vincent TurulaVincent Turula, Ph.D., MBA, Director, Biotherapeutics Pharmaceutical Sciences, Pfizer, Inc.

The manufacture of Antibody-Drug Conjugate clinical trial material is complex as it involves the rapid assembly of many components across a network of specialized service providers. Regardless of the stage of development, from clinical to commercial, production and testing must be coordinated and integrated into robust work streams. The focus of this presentation will be on the challenges that exist in outsourcing ADC manufacture and how a sound strategy and operational consistency can lead to shorten timelines and reduced cost.

4:45 Challenges in ADC Process Development and Scale Up

XavierDespinoyXavier Despinoy, Ph.D., Process Development Manager, Piramal Healthcare Ltd.

The presentation will focus on two standard ADC conjugation processes - partial reduction and  lysine chemistries.  Following general process development and scale-up considerations,  parameters affecting the reactive stages will be reviewed. Development of TFF purification stage and consideration for chromatography will also be discussed.

5:15 End of Conference


5:15- 6:00 Dinner Short Course Registration

6:00 – 8:30 Dinner Short Course*: Analytical Strategies for Comparability in Bioprocess Development 


*Separate registration required


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