Anti Cancer Missile ADC Drugs 3 Design Elements 5 Approved Drugs Multiple Clinical Trialsadc drugs .pdf
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Anti-Cancer Missile ADC Drugs: 3 Design Elements, 5 Approved
Drugs, Multiple Clinical Trials
Antibody-drug conjugates (ADCs) are a new class of targeted drugs consisting of "mAbs, cytotoxic
drugs, and linkers that link the two." The ADC was originally designed to increase the effectiveness
of chemotherapy and reduce its toxicity. Since the antibody is targeted (can recognize cancer cell
surface antigens), the cytotoxic molecules can be selectively "transported" directly into the tumor
cells to exert an anti-cancer effect while avoiding effects on healthy cells.
Recently, due to "AbbVie officially abandoned the R&D of ADC drug Rova-T ", " FDA grants
priority review to antibody-drug conjugate for HER2-positive metastatic breast cancer" and other
news, such ADC drugs, known as "anti-cancer missiles", have once again attracted attention.
So, how is the ADC drug designed? What is the principle of action? What is the current status of
clinical application and development? Which of the research drugs may be approved for marketing
in the future?
1. The Design Element of ADCs
As described above, the components that make up the ADC include tumor antigen-specific
monoclonal antibodies, stable chemical linkers, and potent cytotoxic molecules (also called
payloads). There are many important factors to consider when designing an ADC.
Image source: The Lancet
a) Antibody and target antigen
The desirable properties of the ADC antibody portion include: 1) minimal immunogenicity; 2) high
affinity and avidity for tumour antigen, and efficient internalization (ADC-target antigen complexes
need to be internalized by receptor-mediated endocytosis, allowing them to release potent
cytotoxic loads in cells); 3) has a longer circulating half-life.
In terms of specificity, an ideal target antigen needs to have two characteristics at the same time: 1)
high expression on the surface of target cells; 2) low expression in healthy tissues. In addition, the
ideal shedding of the ADC should be as small as possible to prevent the free antigen from binding
to the antibody in the circulation.
b) Cytotoxic Payload
The cytotoxic payload (molecule/drug) is the final effector component of the ADC. The toxic
payload of the ADC can target either DNA or tubulin.
Viral molecules that target DNA include duocarmycins, calicheamicins, pyrrolobenzodiazepines
(PBDs), and SN-38 (active metabolites of irinotecan). Among them, the action mechanism of
calicheamicins is to induce double bond cleavage, and the action mechanism of duocarmycins and
PBDs is to cause DNA alkylation.
The effect of tubulin inhibitors MMAE (auristatins monomethyl auristatin E) and MMAF
(monomethyl auristatin F) is to inhibit microtubule polymerization, resulting in G2/M phase cell
The basic parameters for selecting an effective toxic payload for the ADC include conjugating,
solubility, and stability. The structure of the selected toxic molecule should be such that it can be
coupled to a linker. In addition, the water solubility of the toxic molecule and the long-term stability
in the blood are important because the ADCs are prepared in an aqueous solution and
The linker is responsible for linking the cytotoxic payload to the mAb and maintaining ADC stability
during the systemic circulation. The chemical nature of the linker and the conjugating site play a
crucial role in the stability, pharmacokinetic and pharmacodynamic properties of the ADC, as well
as the therapeutic window.
An ideal linker must have sufficient stability to ensure that the ADC molecules do not break apart
early, safely circulate through the bloodstream, and reach the target site; they must also be able to
break quickly during internalization to release toxic payloads. According to the release mechanism
of the load, currently available linkers are classified into two types: cleavable and noncleavable.
The former relies on physiological environment to release payloads. A noncleavable linker is a
non-reducible bond with an amino acid residue in a mAb and is, therefore, more stable in the blood;
such a linker (such as a thioether linker) is dependent on the lysosomal degradation of the mAb to
release its payload.
The conjugating characteristics of the connector are critical to controlling the therapeutic window of
the ADC. The drug's drug to antibody ratio (DAR) or the amount of toxic drug attached to the mAb
determines the potency and toxicity of the ADC. Although high drug loading can increase the
potency of the ADC, it also increases off-target effects. In order to overcome the ADC drugs that
produce various DARs in the production process, some studies have adopted innovative methods
of site-specific conjugating to reduce variability, improve conjugating stability and pharmacokinetic
properties, and ultimately produce more ADC products.
2. Action Mechanism of ADCs
Image source: The Lancet
Briefly, the action mechanism of ADC is divided into five steps: 1) the ADC binds to the antigen on
the target cell; 2) the ADC-antigen complex is internalized by endocytosis; 3) the ADC degrades in
the lysosome; 4) the cytotoxic payload (drug) release and function; 5) target cell apoptosis.
Because of the low oral bioavailability of ADCs, such drugs are administered by intravenous
injection. ADCs circulating in the blood first find and bind their target cells. After binding, the ADCantigen complex is internalized by clathrin-mediated endocytosis to form an early endosome
containing an ADC-antigen complex (Fig. 2A). The early endosome eventually develops into a
secondary endosome prior to fusion with the lysosome. For ADCs with cleavable linkers, the
cleavage mechanism (eg hydrolysis, protease cleavage, disulfide bond cleavage) may occur either
in the early endosome or in the secondary endosome, but don’t occur in Lysosomal transport
phase. However, for ADCs with noncleavable linkers, the release of toxic payloads (drugs) is
achieved by complete protein degradation in lysosomes: proton pumps in lysosomes create an
acidic environment that promotes proteases (eg cathepsin-B, plasmin) mediated proteolytic
3. Five FDA Approved Antibody Drug Conjugates
To date, a total of five ADCs have been approved by the FDA and EMA, including: ①brentuximab
vedotin, ②ado-trastuzumab emtansine (T-DM1), ③inotuzumab ozogamicin, ④gemtuzumab
ozogamicin ⑤polatuzumab vedotin-pii. Table 1 summarizes the design, approved indications,
doses, and adverse events of these drugs.
Image source: The Lancet
4. Antibody-Drug Conjugate Clinical Trials
In addition to the five ADC drugs that have been approved for marketing, a large number of ADCs
are currently under clinical development, and the indications include various hematological
malignancies as well as solid tumors. Table 2 lists some promising clinical trials of ADCs.
Image source: The Lancet
As one of the research and development hotspots in the field of medicine, more than 100 ADCs
are currently in different stages of clinical development, and there are hundreds of ongoing clinical
trials. According to the authors of the review, with reference to ClinicalTrials.gov and PubMed, the
number of ADC-related clinical trials and publications has increased this year compared to
2018. Biochempeg provides the most comprehensive media for conjugation research.
In summary, scientists believe that as technology advances, ADCs continue to iterate, and the
choice of targets, linkers, and Cytotoxic Payloads are gradually improving. At the same time, with
the development of immunotherapy, the choice of developing ADC Conjugation therapy is
becoming more and more extensive. Therefore, in the future, ADC-based treatment options are
expected to be used earlier for the treatment of certain types of cancer patients.