Innovative Bioconjugation Technology for Antibody–Drug Conjugates: Proof of Concept in a CD30-Positive Lymphoma Mouse Model

Abstract

To overcome stability and heterogeneity issues of antibody–drug conjugates (ADCs) produced with existing bioconjugation technologies incorporating a maleimide motif, we developed McSAF Inside, a new technology based on a trifunctionalized di­(bromomethyl)­pyridine scaffold. Our solution allows the conjugation of a linker-payload to previously reduced interchain cysteines of a native antibody, resulting in disulfide rebridging. This leads to highly stable and homogeneous ADCs with control over the drug-to-antibody ratio (DAR) and the linker-payload position. Using our technology, we synthesized an ADC, MF-BTX-MMAE, built from anti-CD30 antibody cAC10 (brentuximab), and compared it to Adcetris, the first line treatment against CD30-positive lymphoma, in a CD30-positive lymphoma model. MF-BTX-MMAE displayed improved DAR homogeneity, with a solid batch-to-batch reproducibility, as well as enhanced stability in thermal stress conditions or in the presence of a free thiol-containing protein, such as human serum albumin (HSA). MF-BTX-MMAE showed antigen-binding, in vitro cytotoxicity, in vivo efficacy, and tolerability similar to Adcetris. Therefore, in accordance with current regulatory expectations for the development of new ADCs, McSAF Inside technology gives access to relevant ADCs with improved characteristics and stability.

Adcitmer ® , a new CD56‐targeting monomethyl auristatin E‐conjugated antibody, is a potential therapeutic approach in Merkel cell carcinoma*

“…In the present study, the bioconjugation technology was devoid of a first‐generation maleimide motif, leading to the production of a homogeneous ADC with an optimal average DAR close to 4, which might result in stronger therapeutic activity and reduced toxicities. Moreover, ADC produced with our bioconjugation technology recently demonstrated enhanced stability under thermal stress conditions or in the presence of human serum albumin, when compared to first‐generation ADCs 42 . Thus, the use of site‐specific bioconjugation technology for the generation of Adcitmer ® is likely to improve the toxicity rates of Adcitmer ® over lorvotuzumab mertansine.…”

“…Moreover, ADC produced with our bioconjugation technology recently demonstrated enhanced stability under thermal stress conditions or in the presence of human serum albumin, when compared to first-generation ADCs. 42 Thus, the use of site-specific bioconjugation technology for the generation of Adcitmer â is likely to improve the toxicity rates of Adcitmer â over lorvotuzumab mertansine. Further toxicity studies, such as the determination of the maximum tolerated dose and optimization of the therapeutic scheme, have to be conducted during further development.…”

Antibody–Drug Conjugates as an Emerging Therapy in Oncodermatology

“…Indeed, site-specific conjugation of antibodies has been shown to improve the therapeutic index because it improves ADC pharmacokinetics by reducing the hydrophobicity of the linker-payload as well as prevent the release of payload in blood [48]. Moreover, site-specific conjugation with rebridging of antibody disulfide bonds results in stable and homogeneous ADCs with a controlled number and position of payload, and higher stability characteristics [50].…”

Antibody-Drug Conjugates Containing Payloads from Marine Origin

“…Additional technology has been reported by Juen, Martin, and coworkers, who developed the McSAF Inside Technology based on a trifunctionalized di(bromomethyl)pyridine scaffold capable of bridging the antibody chains at reduced disulfide interchain bonds to incorporate the corresponding linker-drug complex [ 110 , 111 ]. This new strategy allows the control of the DAR and position of the linker-payload resulting in the formation of highly stable and homogeneous ADCs.…”