Treating disease, lowering toxicity: antibody-drug conjugates get the job done
This is great news for cancer therapy, but are we tapping the full potential of ADCs? According to Wang and colleagues from the Scripps Research Institute, these therapies also hold promise to treat T-cell mediated autoimmune disorders like multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and psoriasis (2). For example, T cells attack the insulin-producing beta cells of the pancreas in type 1 diabetes, inflame skin cells with an excess of IL-17 in psoriasis, promote joint inflammation in rheumatoid arthritis, and damage the cells responsible for myelinating neurons in multiple sclerosis (6–9). Inhibiting the destructive T cells that drive these disorders could benefit patients, and there's already a drug on the market able to do so. Dasatinib inhibits kinases that belong to the Src family, such as Lck and Fyn, which play a crucial role in T-cell activation by phosphorylating a range of downstream kinases. It is used clinically to treat myelogenous leukemia (2,10). However, serious side effects like cardiovascular dysfunction and excess fluid build-up in the lungs have complicated its use beyond oncology (2).
The proof is in the T cells: developing ADCs to tackle autoimmune disorders
Wang's team set out to make an ADC to harness dasatinib's clinical promise while reducing its toxicity. First, they needed to identify the antibody best able to deliver dasatinib to T cells without causing nonspecific damage. They considered several antigen targets, including CD3, CD4, and CD70, but eventually settled on CXCR4 due to its high surface expression on human T cells and low expression on non-hematopoietic cells like neutrophils. CXCR4 isn't perfectly selective for T cells—it's known to be expressed by B cells and monocytes—but sending dasatinib to these cells was unlikely to cause serious side effects. Moreover, previous research demonstrated that cells efficiently internalized antibodies bound to CXCR4. Luckily, the team had already generated an antibody with high specificity and affinity for this antigen. They humanized this anti-CXCR4 antibody to avoid a potential immune response and then turned their attention to connecting the dots of their ADC (2).
Small molecule drug with big therapeutic potential? Check. Specific antigen to target that small molecule drug to the cells of interest? Check. Adding a spacer arm to connect the two elements was the last piece of the puzzle, so Wang and his colleagues designed two potential linkers. The team then harnessed SoluLINK® conjugation chemistry to synthesize two unique ADCs: dasatinib + linker #1 + anti-CXCR4 and dasatinib + linker #2 + anti-CXCR4. Different types of linkers have different chemical properties and can change the efficacy of drug release, internalization, and the amount of time a drug resides in the cell. While Wang's group found that both of their ADCs suppressed T-cell activation and cytokine secretion, one candidate more potently inhibited the release of the critical signaling molecules TNFα, IFNγ, and IL-2. Wang's group further demonstrated that their winning ADC candidate blocked the phosphorylation typically mediated by Lck, one of the Src family kinases known to trigger T-cell activation, without causing loss of T-cell viability (2). While they caution that these results need to be confirmed in vivo, their study demonstrated that bioconjugation might soon open the door to novel treatment options for patients with autoimmune disorders.
Beyond ADCs: the power of bioconjugation
The development of novel ADCs is just one example of bioconjugation driving scientific innovation. This versatile technique links many types of biomolecules, such as oligonucleotides, proteins, peptides, or antibodies, to additional molecules, like enzymes, to yield a pairing with unique functionality. One widely used example is fluorophore-conjugated antibodies. These versatile hybrids can be used in a wide range of applications, including protein isolation and quantification, cellular pathway perturbation, and in proteomics and genomics platforms. If you're interested in learning more about how bioconjugation can help you push your research further, check out this recent webinar from Vector Laboratories or take a look at our Bioconjugation Resource guide.
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- Wang RE, et al. 2015. An Immunosuppressive Antibody–Drug Conjugate. Journal of the American Chemical Society
- Li F, et al. 2017. Bioconjugate Therapeutics: Current Progress and Future Perspective. Molecular Pharmaceutics
- Joubert N, et al. 2020. Antibody–Drug Conjugates: The Last Decade. Pharmaceuticals (Basel)
- Biopharma PEG. 2021. FDA approved antibody-drug conjugates up to 2021.
- Hawkes JE, et al 2017. Psoriasis Pathogenesis and the Development of Novel Targeted Immune Therapies. The Journal of Allery and Clinical Immunology
- Hull CM, et al 2017. Regulatory T Cell Dysfunction in Type 1 Diabetes: What's Broken and How can we Fix it? . Diabetologia
- Kaskow BJ, et al 2018. Effector T Cells in Multiple Sclerosis. Cold Spring Harbor Perspectives in Medicine
- Skapenko A, et al 2005. The Role of the T Cell in Autoimmune Inflammation. Arthritis Research & Therapy
- Palacios EH, et al 2004. Function of the Src-Family Kinases, Lck and Fyn, in T-Cell Development and Activation. Oncogene