The manufacturing considerations of bispecific antibodies

ABSTRACT

Introduction

Antibody therapies have made huge strides in providing safe and efficacious drugs for autoimmune, cancer, and infectious diseases. These bispecific antibodies can be assembled from the basic building blocks of IgGs, resulting in dozens of formats.

Areas covered

It is important to consider the manufacturability of these formats early in the antibody discovery phases. Broadly categorizing bispecific antibodies into IgG-like, fragment-based, appended, and hybrid formats can help in looking at early manufacturability considerations.

Expert opinion

Ideally, bispecific antibody manufacturing should contain a minimal number of steps, with processes that give high yields of protein with no contaminants. Many of these have been determined for the fragment-based bispecific blinatumomab and the IgG-like bispecifics from hybridomas. However, for new formats, these need to be considered early in the research and development pipeline. The hybrid formats offer an unusual alternative in generating high pure yields of bispecific molecules if the engineering challenges can be deciphered.

KEYWORDS:

• Bispecific antibodies
• manufacturing bispecific antibodies
• light chain mispairing
• appended bispecific formats
• IgG-like bispecific formats
• fragment-based bispecific formats
• bispecific format
• cell-free expression
• quadroma
• mRNA-based antibodies

Article highlights

• Bispecific antibody engineering has boomed in the last 10 years with the FDA approval of three bispecific molecules for the treatment of disease.

• This has led to the further development of bispecific antibodies, with over 200 antibodies in clinical trials, all for a variety of diseases and with different bispecific modalities.

• For manufacturing, bispecific antibody molecules can be thought of as one of four broad categories: IgG-like, fragment-based, appended, and hybrid molecules.

• Each category has its own unique manufacturing solutions that need solving to enable these molecules to succeed in the clinic and reach FDA approval.

• The hybrid antibody bispecific format is a good compromise between all these modalities, if the protein engineering solutions to improve their expression and stability can be determined.

• We encourage the early engagement of R&D with manufacturing teams to ensure that all formats in development can be successfully manufactured at scale.

This box summarizes key points contained in the article.

Declaration of interests

Z Jawad is the CEO and founder of Creasallis Ltd. DJ Underwood and J Bettencourt are employees of Agenus Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.