US FDA offers guidance on when two mAbs should be considered the same

The FDA says that typically, two protein drugs would be considered the same “if the only differences in structure between them were due to posttranslational events or infidelity of translation or transcription or were minor differences in amino acid sequence​.” But for mAb (monocolonal antibody) drugs, unique considerations applicable to antibody molecules need to be analysed under the Orphan Drug regulations.

For the purpose of this guidance, the FDA defines a monoclonal antibody as a clonal product defined as any intact antibody, antibody fragment, conjugate, fusion protein, bispecific, or multi-specific antibody that contains a variable heavy and variable light pair, single V (variable) domain, or combinations of single V domains where the CDRs (complementarity determining regions) form the antigen binding site.

FDA intends to interpret the applicable regulatory provisions such that two mAbs would be considered to be the same drug if the CDRs’ amino acid sequences were the same or if there were only minor amino acid differences between them. Other potentially important amino acid differences outside the CDRs, or differences due to glycosylation patterns or posttranslational modifications, “would not necessarily cause the products to be considered to be different​,” the agency says.

For the purpose of determining sameness of unmodified monoclonal antibodies under the Orphan Drug Act, the agency will consider the CDRs of the heavy and light chain variable regions to be the principal molecular structural features of a mAb product.

Determinations on sameness will be made a case-by-case basis, FDA clarifies, noting that the types of information that would be useful in making such a determination include the sequence of the heavy and light chain variable regions of the product, any modifications in antibody sequence, and whether any particular residues have been established to be important for antigen binding.

For antibody conjugates, FDA intends to interpret the applicable regulatory provisions such that the determination of sameness of mAbs “will be based on a determination of sameness of the monoclonal antibody element and sameness of the functional element of the conjugated molecule​.”

For certain potential changes that sponsors may make in areas outside the CDRs in mAbs, FDA intends to consider such changes as not necessarily causing two mAbs with the same CDRs to be different drugs.

The agency also notes that drugmakers may focus on two regions – framework and constant regions. Changes on the framework region can include “humanizing a nonhuman-derived monoclonal antibody or engineering certain framework residues that are important for antigen contact or stabilizing the binding site​.”

Constant region differences include “changing the class or subclass of the constant region, changing specific amino acid residues that might alter an effector function such as Fc receptor binding, or changing the species from which the constant region is derived​.”

The FDA concludes that intact mAbs and antibody fragments with the same CDR sequences or with only minor amino acid differences between them, will not be considered to be different drugs.