Despite the increasing number of ADC approvals, there are still challenges for ADCs that have demonstrated superior safety and efficacy in the clinic. What're the challenges?
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Adc drugs some challenges to be solved
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ADC Drugs: Some Challenges To Be Solved
Antibody-drug conjugates (ADCs), which use antibodies to selectively deliver cytotoxic
drugs to the tumor site, are currently in rapid development. To date, a total of
twelve ADCs have been approved by the FDA, they are Kadcyla, Adcetris, Besponsa,
Mylotarg, Lumoxiti, Polivy, Padcev, Trodelvy, Enhertu,
Blenrep, ZYNLONTA and Tivdak. In addition, there are currently more than 80 ADCs
under investigation being evaluated in approximately 150 active clinical
trials. Despite the increasing popularity of ADCs, scaling up their therapeutic index (better
efficacy and less toxicity) remains a challenge.
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ADC can't prove itself stronger
Despite the increasing number of ADC approvals, there are still challenges for ADCs that
have demonstrated superior safety and efficacy in the clinic. An unexpected challenge
faced by many developers during clinical evaluations is the inability of ADCs to
demonstrate benefit compared to controls, such as MM-302. MM-302 is an anti-HER2
monoclonal antibody conjugated to doxorubicin.
The Phase II HERMIONE trial (NCT02213744) was discontinued due to a lack of benefit
from a placebo treatment. Another ADC that reported a similar situation was
Rovalpitumab tesirine (RovA-T), encouraging results from the Phase I trial reported 18%
ORR in assessable patients, 38% ORR in patients with high DLL3 expression
(NCT01901653). However, safety and efficacy issues were raised due to the results of
the Phase II trial TRINITY (NCT02674568), which did not meet the primary endpoint and
reported high toxicity rates. The most common event in patients was pleural effusion,
which was thought to be toxic in association with PBDE dimers. Ultimately, results from
the Phase III trials TAHOE (NCT03061812) and MERU (NCT03033511) resulted in
AbbVie completely discontinuing the development of RovA-T, with a lack of survival
benefit compared to the control group.
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The design of ADC drug
Off-target toxicity of ADCs
One of the major challenges of ADCs is off-target toxicity, which is caused by the
premature release of cytotoxic small molecules into the bloodstream. Antibodies are an
awkward vehicle for transport, difficult to navigate through the tumor's alleys, and it is
estimated that only 0.1% of the drug reaches the tumor tissue. In order to ensure that the
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other 99% of highly toxic warheads do not bring systemic toxicity, the chemical link
between the warhead and the antibody must be sufficiently stable. However, in order to
release the warhead in the cell without being too stable, this obviously brings trouble to
drug design.
The associated increased risk depends on the toxicity profile associated with cytotoxic
small molecules. Off-target toxicities of maytansine (DM1) were hepatotoxicity and
thrombocytopenia. MMAE was associated with the likelihood of peripheral neuropathy,
neutropenia, and anemia. MMAF was associated with ocular toxicity. In terms of the
metabolic characteristics of ADC, the hydrophobicity of ADC increases the clearance rate
due to the high drug load of hydrophobic small molecules. An in vivo study involving a
xenograft model compared the effect of a high dose of MMAE with different DARS (2, 4,
and 8) conjugation against CD30 mab on ADC clearance. The results showed that the
higher the drug loading, the higher the clearance rate. In this study, ADCs with a DAR of
8 were cleared fastest.
Aggregation of ADCs
In addition, ADCs are easy to aggregate. ADC aggregation leads to modifications that
reduce its ability to bind antigens.
Protein aggregation is a major obstacle to ADC development. It can occur at every
stage as well as during transportation and long-term storage. The
aggregation is immunogenic. In addition, protein aggregation can lead to product loss.
Overall, any chemical or physical degradation can lead to structural changes in ADCs and
lead to excessive protein aggregation. There are various other factors that can cause
aggregation, such as frequent freezing/thawing, high protein and salt concentrations,
elevated temperature, or low pH. In addition, most payloads are hydrophobic, and binding
the payload at a high DAR on the protein surface can lead to excessive protein
aggregation, hindering the successful development of ADCs. In some ADCs, the payload
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binds to Cys residues after breaking existing disulfide bonds, and
hydrophobic-hydrophobic interactions increase.
Drug resistance of ADCs
Another challenge factor is drug resistance. The internalization of the payload and its
efficacy are mainly affected by acquired resistance mechanisms, such as down-regulation
of tumor cell antigen expression. Drug resistance occurs when a treatment fails or
becomes less effective, or when tumor cells escape. Drug resistance can arise at the start
of treatment or after drug treatment.
There are many mechanisms by which drug resistance arises, some of which include:
down-regulation of antigen level expression, drug efflux pumps, endocytosis and
migration, defective lysosomal function, altered signaling pathways, and dysregulated
apoptosis.
Immunogenicity of ADCs
With the increase in the types and wide application of macromolecular protein drugs, the
related immunogenicity problems have gradually surfaced. Protein drugs have
potential factors to induce immunogenicity, the consequences of which may affect efficacy
and even be life-threatening. Antibody-drug conjugates (ADCs) have the same
immunogenicity as antibody drugs, and their immunogenicity risks affect the safety and
effectiveness of the drugs for patients, and may even bring fatal new diseases to patients
due to ADA and endogenous protein cross. (See: Immunogenicity of ADC)
Conclusion
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Along with the success and excitement of the ADC development process, there also
have its complexities and limitations. This is an era of innovative drugs, with newer
iterations of different technologies, and ADCs need more extensive clinical coverage and
confirmation as more questions are studied in depth.
In the future, ADC drugs will have a huge potential in the anti-tumor market. Biopharma
PEG is a worldwide leader of PEG linker supplier that offers a wide array of different ADC
linkers to empower our customer's advanced research.
References:
[1] Antibody–Drug Conjugates: The Last Decade,Pharmaceuticals 2020, 13, 245,1-31
[2] Targeting cancer with antibody-drug conjugates: Promises and challenges. MABS,2021, VOL. 13,
NO. 1,
[3] The Chemistry Behind ADC. Pharmaceuticals (Basel). 2021 May; 14(5): 442.
[4] Immunogenicity of antibody-drug conjugates: observations across 8 molecules in 11 clinical trials.
Bioanalysis. 2019 Sep;11(17):1555-1568.
[5] Mechanisms of Resistance to Antibody–Drug Conjugates. Mol Cancer Ther; 15(12) December 2016