Regulatory considerations in the design, development and quality of monoclonal antibodies and related products for the diagnosis and treatment of cancer

Abstract

Over 160 therapeutic and in vivo diagnostic monoclonal antibodies have been approved by the US FDA since the first monoclonal antibody, muromonab, was approved in 1986. Approximately 42% of these approvals were for the treatment or in vivo diagnosis of oncology indications, although some products are no longer marketed. This review will look at the history of monoclonal antibody development and approvals, discuss current antibody-based modalities, regulatory considerations for engineering approaches, critical quality attributes for different modalities, immunogenicity of mAbs across oncology products, and the future directions for development of therapeutic and diagnostic monoclonal antibody-based products.

Keywords: Fc-engineering; antibody drug conjugate; antibody-fusion protein; bispecific antibody; immunogenicity; isotypes; monoclonal antibody; radioimmunoconjugate.

Figure 1

All FDA approved monoclonal antibodies. Products listed indicate firsts for oncology products. Numbers above the bars indicate the number of oncology approvals in that year. The graph does not include the approvals of rituximab hyaluronidase or the combination of pertuzumab, trastuzumab and hyaluronidase as the individual components are not novel.

Figure 2

Trends in bispecific antibodies and antibody-drug conjugate IND submissions for oncology indications. (A) Bispecific antibody IND submissions between 2006 through October 2023. (B) Trends in ADC payloads from 2012 through October 2023.

Figure 3

Immunogenicity of monoclonal antibodies approved for oncology indications. Incidence of ADA is shown for oncology mAbs of murine, chimeric, humanized, or human origin and includes the incidence for those mAbs that are also approved for non-oncology indications. Murine mAbs: Incidence of ADA for ibritumomab and tositumomab, red circles. Chimeric mAbs: Incidence of ADA for rituximab and rituximab hyaluronidase in oncology, red circles, and for rituximab in autoimmune indications, purple circles. Humanized mAbs: Incidence of ADA for alemtuzumab in oncology, red circle and an autoimmune indication, purple circle. Incidence of ADA of CKI mAbs; pembrolizumab, atezolizumab, dostarlimab, retifanlimab, and toripalimab, blue circles. Human mAbs: Incidence of ADA for ofatumumab in oncology, red circle and an autoimmune indication, purple circle. Incidence of ADA of CKI mAbs when used as monotherapy; ipilimumab, nivolumab, durvalumab, avelumab, cemiplimab, blue circles. Incidence of ADA of CKI mAbs when used in combination; ipilimumab, nivolumab and durvalumab, green circles. The incidence of ADA for a CKI mAb can vary per indication. For those with multiple indications, only the highest incidence of ADA seen with monotherapy or in combination is shown.