FDA Provides Key Guidance for Biotech Products

Bispecific Antibody Development Program Guidance

BY Kurt Brorson, Ph.D., Ken Draper, Ph.D., William Kelce, Ph.D., Regulatory Consulting - 6.3.19

Earlier this month FDA released a draft guidance called “Bispecific Antibody Development Programs”.  This is a welcome addition to FDA’s set of guidance documents for biotechnology products. 

This draft guidance covers manufacturing (CMC/quality), nonclinical, and clinical recommendations to assist in the development of the complex product class of bispecific antibodies. Bispecific antibodies are genetically-engineered, recombinant antibodies that consist of two distinct binding domains (variable regions or complementarity-determining region surfaces) capable of binding two different antigens or two different epitopes of the same antigen. 

There can be a strong scientific rationale for targeting multiple disease-modifying molecules with one drug for a specific disease, for example retargeting immune cells like T lymphocytes to recognize a specific target, like a tumor cell.  Other mechanisms can be imagined, for example, sequestration of two soluble cytokines at the same time or binding different epitopes of the same tumor or viral antigen for more efficient clearing.

The guidance emphasizes existing CMC approaches for biotechnology products like consistent high-quality bioprocessing, process validation, and a robust testing/stability program and proposes more novel approaches for bispecific antibodies like the need to evaluate both variable regions separately for antigen binding (e.g., on- and off-rates).  The guidance also recommends a description of how the two separate chains are best combined to create a consistent bi-specific hybrid antibody with two antibody specificities, not simply a Poisson distribution of homo and heterodimeric forms.  Potency assay development should address functional aspects of both antibody variable regions, preferably in a bioassay that involves both targets, whether they are cells or soluble proteins.  Protein stability and formulation may also be a complex issue warranting careful monitoring and control, for example to prevent antibody aggregation and precipitation.

This guidance suggests that bispecific antibodies may be sorted to two distinct categories (i.e., those that function to bridge two target cells and those that that bridge other combinations, such as two cytokines or two sites on the same target molecule/cell). In the latter instance, binding to both targets at the same time may not be required for efficacy. Special considerations for the bispecific antibody development program will be required, including determining whether both targets need to be engaged simultaneously, determining the affinity and on- and off-rates of each arm for its cognate target, and determining potential synergy when binding both targets.

Nonclinical data supplied to support the scientific rationale will depend on the particular drug and clinical indication and could potentially be derived from either animal studies or in vitro assays. The scope of the nonclinical program, including pharmacology studies, species selection for toxicology studies, general toxicology, and reproductive toxicology, is expected to be similar to that for monoclonal antibodies directed against a single target. In vitro and in vivo pharmacology studies will be needed to generate nonclinical data supporting the scientific rationale of the bispecific antibody and will be useful in selecting the first-in-human (FIH) dose. The standard nonclinical approaches to support the safety of the starting dose in the clinical trial will be appropriate, although FIH dose selection should always be discussed with the appropriate FDA clinical review division regardless of the rationale chosen.

Parexel stands committed to help clients navigate regulatory aspects of this revolutionary but complex new technology.  In addition, this is an evolving field where interested parties can have an impact on the ultimate regulatory policy.  Biotech firms and other stakeholders have until June 18, 2019 to comment on this important new document, by uploading comments under docket number 2019-07930, and Parexel urges them to become involved.


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