Immunogenicity of Antibody Drug Conjugates: Bioanalytical Methods and Monitoring Strategy for a Novel Therapeutic Modality

Abstract

Abstract. Immunogenicity (the development of an adaptive immune response reactive with a therapeutic) is a well-described but unwanted facet of biotherapeutic development. There are commonly applied procedures for immunogenicity risk assessment, testing strategies, and bioanalysis. With some modifications, these can be applied to new biotherapeutic modalities. For novel therapies such as antibody-drug conjugates (ADCs), the unique structural components may contribute additional complexities to both immunologic responses and bioanalytical methods. US product inserts (USPIs) for two commercially available ADCs detail the incidence of immunogenicity; however, the body of literature on immunogenicity of ADCs is limited. We recently participated in a conference session on this topic (Annual meeting of the American Association of Pharmaceutical Scientists, held November 2013 in San Antonio, TX, USA. The meeting featured the Symposium: Immunogenicity Assessment for Novel Antibody Drug Conjugates, Nonclinical to Clinical) which prompted an effort to share our perspectives on how immunogenicity risk assessment, testing strategies, and bioanalytical methods can be adapted to reflect the complexity of ADC therapeutics.

Assessment of clinical immunogenicity of inotuzumab ozogamicin in patients with non-Hodgkin lymphoma and acute lymphoblastic leukemia

“…For these reasons, comparing the incidence of antibodies to InO in the studies described herein with the incidence of antibodies to other products may be misleading. Published data show that the immunogenicity binding antibody rates range from 0% to 30% (Hock et al, 2015). In addition, CarrascoTriguero reported a 4.3% incidence rate in a phase 3 clinical study of Kadcyla, (ado-trastuzumab emtansine [T-DM1]); however, the neutralizing antibody rate was not published (Carrasco-Triguero et al, 2013).…”

Antibody–Drug Conjugates as Cancer Therapeutics: Past, Present, and Future

“…64 With ADCs, ADAs may develop against the mAb, linker, or payload. The risk of developing ADAs depends on many product-, patient-, and disease-related factors and is likely influenced by patient immunological status.…”

“…The risk of developing ADAs depends on many product-, patient-, and disease-related factors and is likely influenced by patient immunological status. [64][65][66] Current regulatory guidelines for assessment of immunogenicity of therapeutic proteins can be applied to ADCs. 65,66 A multitiered strategy for immunogenicity assessment is recommended, starting with screening assays to identify ADA-positive samples and patients, followed by confirming the presence of ADA, procedures to characterize antibody domain specificity, and functional assays to investigate the neutralizing capacity of the ADA.…”

“…A survey of published immunogenicity data for 9 ADCs found low ADA incidence (0% to 2.6%) for the 6 ADCs with data derived primarily from phase 1 studies. 64 However, these data may underestimate the true incidence of ADAs to these ADCs, because treatment duration and number of doses administered are relatively low in these early-phase studies. The incidence of ADAs for gemtuzumab ozogamicin (now withdrawn from the US market) was 1.1% among 182 tested patients.…”

“…The incidence of ADAs for gemtuzumab ozogamicin (now withdrawn from the US market) was 1.1% among 182 tested patients. 64,67 Among 156 patients treated with brentuximab vedotin, approximately 7% developed persistent ADAs, and 30% developed transiently positive ADAs; 36 of 58 patients tested for the presence of neutralizing antibodies (62%) had 1 or more positive samples. 68,69 Based on population PK analysis, brentuximab vedotin clearance was 18% higher in ADApositive patients, but data simulations suggested this increase was not clinically meaningful.…”