Antibody drug conjugates as targeted cancer therapy: past development, present challenges and future opportunities

Abstract

Antibody drug conjugates (ADCs) are promising cancer therapeutics with minimal toxicity as compared to small cytotoxic molecules alone and have shown the evidence to overcome resistance against tumor and prevent relapse of cancer. The ADC has a potential to change the paradigm of cancer chemotherapeutic treatment. At present, 13 ADCs have been approved by USFDA for the treatment of various types of solid tumor and haematological malignancies. This review covers the three structural components of an ADC-antibody, linker, and cytotoxic payload-along with their respective structure, chemistry, mechanism of action, and influence on the activity of ADCs. It covers comprehensive insight on structural role of linker towards efficacy, stability & toxicity of ADCs, different types of linkers & various conjugation techniques. A brief overview of various analytical techniques used for the qualitative and quantitative analysis of ADC is summarized. The current challenges of ADCs, such as heterogeneity, bystander effect, protein aggregation, inefficient internalization or poor penetration into tumor cells, narrow therapeutic index, emergence of resistance, etc., are outlined along with recent advances and future opportunities for the development of more promising next-generation ADCs.

Keywords: ADC; Cancer treatment; DAR; Linkers; Site specific conjugation; Targeted therapy.

Fig. 1

Schematic representation of antibody-drug conjugate

Fig. 2

ADC conjugated to payload (Doxorubicin) through pH sensitive hydrazone linker which gets cleaved in the acidic environment between pH 4–5

Fig. 3

ADC conjugated to payload (MMAE) through peptide (valine-citrulline) linker: Amide bond between valine-citrulline linker and p-amino benzyl alcohol (PABC) is cleaved by lysosomal enzyme and resultant moiety undergoes spontaneous self-immolation of the PABC portion through 1,6-elimination process to release the free payload, MMAE into the tumor cell

Fig. 4

ADC conjugated to payload (DM4) through disulfide linker: Disulphide bond is reduced by high concentration of reduced glutathione (GSH) within tumor cell and payload gets released as active metabolite

Fig. 5

ADC conjugated to payload (SN38) through β-glucuronide linker: Release mechanism involves initial de-glucuronidation using enzyme β-glucuronidase followed by 1,6-elimination, decarboxylation, and lastly cyclization of the dimethylethylene diamine (DMED, self-immolative spacer) carbamate to liberate free payload, SN38

Fig. 6

ADC conjugated to payload (DM1) through non-cleavable (MCC) linker: Release mechanism involves complete lysosomal proteolytic degradation of the antibody after internalization into the cell which releases the active metabolite of payload, lysine-MCC-DM1

Fig. 7

Structures of various payloads used in ADCs