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Review
. 2019 Jan-Mar;11(1):3-23.

Antibody-Drug Conjugates: Possibilities and Challenges

Mohammad-Reza Nejadmoghaddam  1   2 , Arash Minai-Tehrani  2 , Ramin Ghahremanzadeh  2 , Morteza Mahmoudi  1 , Rassoul Dinarvand  1   3 , Amir-Hassan Zarnani  4   5   6
Affiliations
Review

Antibody-Drug Conjugates: Possibilities and Challenges

Mohammad-Reza Nejadmoghaddam et al. Avicenna J Med Biotechnol. 2019 Jan-Mar.

Abstract

The design of Antibody Drug Conjugates (ADCs) as efficient _targeting agents for tumor cell is still in its infancy for clinical applications. This approach incorporates the antibody specificity and cell killing activity of chemically conjugated cytotoxic agents. Antibody in ADC structure acts as a _targeting agent and a nanoscale carrier to deliver a therapeutic dose of cytotoxic cargo into desired tumor cells. Early ADCs encountered major obstacles including, low blood residency time, low penetration capacity to tumor microenvironment, low payload potency, immunogenicity, unusual off-_target toxicity, drug resistance, and the lack of stable linkage in blood circulation. Although extensive studies have been conducted to overcome these issues, the ADCs based therapies are still far from having high-efficient clinical outcomes. This review outlines the key characteristics of ADCs including tumor marker, antibody, cytotoxic payload, and linkage strategy with a focus on technical improvement and some future trends in the pipeline.

Keywords: Antibody-Drug; Cancer therapy; Cytotoxic drugs; Monoclonal antibodies; Nanomedicine.

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Conflict of interest statement

Conflict of Interest The authors declare that they have no competing interests.

Figures

Figure 1.
Figure 1.
Schematic representation of ADC, showing the main components of an ADC and its cell cytotoxicity mechanism. Clinical efficacy of ADCs is determined by fine-tuning combination of tumor antigen, _targeting antibody, cytotoxic payload and conjugation strategy (a). ADC binds to tumor _target cell surface antigens (b) leading to trigger a specific receptor mediated internalization (c). The internalized ADCs are decomposed to release cytotoxic payloads inside the tumor cell either through its linkage/linker sensitivity to protease, acidic, reductive agents or by lysosomal process, leading to cell death (d).
Figure 2.
Figure 2.
Main considerations in selecting tumor markers for ADC design and development.
Figure 3.
Figure 3.
Main considerations in producing antibodies for ADC design and development.
Figure 4.
Figure 4.
Kd frequency distribution (a) and histogram data (b) of current ADC in clinical development (Table S1, n=13). Antibody affinities (Kd) that have been used in current ADC in clinical development were classified into either ≤10 nM or ≥10 nM groups. The average Kd and standard deviation of ≤10 nM group was 1.12 and 1.3 and for ≥10 nM group was 39.9 and 28.2, respectively. Median Kd of ≤10 nM group and ≥10 nM groups was 0.7 and 40.5, respectively. Average Kd was significantly different between two groups (p<0.05). The frequency distributions of Kd in ≥10 nM groups are more than ≤10 nM groups (a).
Figure 5.
Figure 5.
Main considerations in choosing cytotoxic payloads for ADC design and development.
Figure 6.
Figure 6.
Main considerations for linking cytotoxic payload to antibodies in ADC design and development.
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