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Review
. 2020 Sep 14;13(9):245.
doi: 10.3390/ph13090245.

Antibody-Drug Conjugates: The Last Decade

Nicolas Joubert  1 , Alain Beck  2 , Charles Dumontet  3   4 , Caroline Denevault-Sabourin  1
Affiliations
Review

Antibody-Drug Conjugates: The Last Decade

Nicolas Joubert et al. Pharmaceuticals (Basel). .

Abstract

An armed antibody (antibody-drug conjugate or ADC) is a vectorized chemotherapy, which results from the grafting of a cytotoxic agent onto a monoclonal antibody via a judiciously constructed spacer arm. ADCs have made considerable progress in 10 years. While in 2009 only gemtuzumab ozogamicin (Mylotarg®) was used clinically, in 2020, 9 Food and Drug Administration (FDA)-approved ADCs are available, and more than 80 others are in active clinical studies. This review will focus on FDA-approved and late-stage ADCs, their limitations including their toxicity and associated resistance mechanisms, as well as new emerging strategies to address these issues and attempt to widen their therapeutic window. Finally, we will discuss their combination with conventional chemotherapy or checkpoint inhibitors, and their design for applications beyond oncology, to make ADCs the magic bullet that Paul Ehrlich dreamed of.

Keywords: ADC; antibody–drug conjugate; bioconjugation; cancer; combination therapies; linker; payload; resistance.

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Conflict of interest statement

Alain Beck is an employee of Pierre Fabre, Charles Dumontet has received research funding from Roche and is a founder of Mablinks. All authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1
Figure 1
Schematic representation of the first and second generation FDA-approved ADCs: Mylotarg®, Adcetris®, Kadcyla®, Besponsa®, Polivy® and Padcev®.
Scheme 1
Scheme 1
Mylotarg® or Besponsa® mechanism of action: (1) binding to the specific antigen (Ag), followed by internalization of the ADC-Ag complex through a clathrin-dependent mechanism; (2) transfer to endosomes; (3) the acid-sensitive hydrazone of the linker is cleaved in early endosome and lysosome; (4) transfer of pro-calicheamycin into the lysosome; (5) cleavage of the disulfide bridge to give calicheamycin then (6) transfer of calicheamycin into the cytoplasm and (7) transfer of calicheamycin into the nucleus. (8) Alternatively to 7, transfer of calicheamycin into the cytoplasm then (9) diffusion of calicheamycin into neighboring cancer cells to obtain a cytotoxic bystander effect and (10) all the previous steps lead to cell death.
Scheme 2
Scheme 2
Kadcyla® mechanism of action: (1) binding on its specific HER2 Ag, followed by internalization of the T-DM1-HER2 complex by a clathrin-dependent mechanism; (2) transfer to the endosome then (3) to the lysosome; (4) complete trastuzumab digestion to release the active metabolite, LYS-MCC-DM1 and (5) transfer into the cytoplasm. (6) due to its charge at the physiological pH, the active metabolite is unable to cross the cell membrane, therefore it does not elicit any bystander killing effect, and transfer to tubulin. (7) All the preceding steps lead to HER2-positive cancer cell death.
Scheme 3
Scheme 3
Adcetris®, Polivy® or Padcev® mechanism of action: (1) binding to a specific Ag, followed by internalization of the ADC-Ag complex according to a clathrin-dependent mechanism; (2) transfer to the endosomes then (3) to the lysosomes; (4) linker cleavage in the lysosomes takes place between the peptide sequence (ValCit) and the self-immolative spacer (PAB); (5) transfer of MMAE into the cytoplasm; (6) MMAE can also be released before internalization, then (7) enter the targeted cell (or a nearby tumor cell) and (8) intracellular or extracellular MMAE release is followed by tubulin targeting. In parallel to 8, (9) diffusion of another MMAE in neighboring tumor cells not targeted by the ADC to obtain a bystander killing effect and (10) all the previous steps lead to tumor cell death.
Figure 2
Figure 2
Homogeneous ADCs with a drug-to-antibody ratio (DAR) 2 generated through antibody engineering and site-specific bioconjugation.
Figure 3
Figure 3
Homogeneous ADC generated by deglycosylation (position Q295), in the presence of PNGase F, followed by a bioconjugation mediated by transglutaminase (position 297). The azide immunoconjugate, in the presence of DBCO-linker-MMAE, allows the production of a homogeneous ADC with a DAR 2.
Figure 4
Figure 4
Homogeneous ADC with a DAR 4 obtained by complete reduction (TCEP) of all 4 interchain disulfide bridges followed by a site-specific bioconjugation reaction via a dibromomaleimide linker (DBM).
Figure 5
Figure 5
Homogeneous SDC (scFv-drug conjugate) with a DAR 1 obtained by reduction (TCEP) of the C-terminal intrachain disulfide bridge followed by a site-specific bioconjugation reaction via a dithiophenylmaleimide linker (DSPh).
Figure 6
Figure 6
Homogeneous ADC with a DAR 4 comprising a biparatopic anti-HER2 antibody conjugated to a tubulysin derivative via a classical maleimidocaproic linker.
Figure 7
Figure 7
Immunoconjugates IgG(F8)-SS-DM1 and SIP(F8)-SS-DM1 with a DAR 2, and formula of the payload DM1.
Figure 8
Figure 8
Homogeneous ADC with a DAR 2 carrying talirine including a dimeric derivative of pyrrolobenzodiazepine (PBD; SGN-1882).
Figure 9
Figure 9
Homogeneous ADCs with a DAR 2 carrying tesirine including a dimeric derivative of PBD (SGN-3199).
Figure 10
Figure 10
Homogeneous ADC carrying an anthracycline derivative (PNU-159682).
Figure 11
Figure 11
HDP-101 formula, ADC with a DAR 2, resulting from the site-specific conjugation of an α-amanitin analog (HDP 30.2115) onto an anti-BCMA Thiomab via a cathepsine B-sensitive linker.
Figure 12
Figure 12
Formula of mirvetuximab soravtansine, antifolate R1 antibody conjugated to DM4 via a non-cleavable linker.
Figure 13
Figure 13
Formula of depatuximab mafodotin and Blenrep® (belantamab mafodotin-blmf), antibodies conjugated to MMAF via a non-cleavable linker.
Figure 14
Figure 14
SYD985 formula, anti-HER2 trastuzumab conjugated to seco-DUBA via a cleavable linker sensitive to cathepsin B.
Figure 15
Figure 15
Trodelvy® (sacituzumab govitecan or IMMU-132) formula, ADC with a DAR 7.6, resulting from anti-TROP-2 antibody conjugation to SN-38 via an acid-sensitive cleavable linker.
Figure 16
Figure 16
Enhertu® (fam-trastuzumab deruxtecan-nxki or DS-8201a) formula, ADC with a DAR 7.7, resulting from anti-HER2 trastuzumab conjugation to exatecan DX-8951 via a linker sensitive to proteolysis.
Figure 17
Figure 17
(a) Formula of an ADC resulting from the conjugation of dexamethasone onto an anti-CD163 mAb, with a DAR of 4. (b) Formula of an ADC resulting from the site-specific conjugation of fluticasone propionate onto an anti-CD74 IgG4 mutated mAb, with a homogeneous DAR of 2. (c) Formula of an ADC resulting from the conjugation of a dexamethasone analog onto anti-TNF-α adalimumab, with a DAR of 2 or 4.
Figure 18
Figure 18
(a) Formula of an ADC resulting from the stochastic conjugation of dasatinib onto an optimized anti-CXCR4 mAb (HLCX) through a gluthathione sensitive linker, with an average DAR of 3. (b) Formula of an ADC resulting from the site-specific conjugation of a LXR agonist onto an anti-CD11a mutated mAb, with a homogeneous DAR of 2.
Figure 19
Figure 19
RG7861 formula, ADC with a DAR 2, resulting from the site-specific conjugation of rifalogue onto an anti-wall-teichoic acid (WTA) Thiomab via a cathepsine B-sensitive linker, targeting the surface of Staphylococcus aureus.
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