The endocytosis mechanism of ADC drugs: Part III


Posted October 15, 2021 by beauty33

CD22 is a 140 kDa transmembrane glycoprotein, which, like CD33, is also a member of the Siglec family and has many shared structural features. CD22 is much larger than CD33 because it has multiple Ig domains and ITIM/ITIM-like motifs.
 
CD22
CD22 is a 140 kDa transmembrane glycoprotein, which, like CD33, is also a member of the Siglec family and has many shared structural features. CD22 is much larger than CD33 because it has multiple Ig domains and ITIM/ITIM-like motifs. The expression of CD22 is limited to B cells, and the expression level of CD22 is elevated in most blasts of various B cell malignancies (including ALL).

CD22 undergoes endocytosis through CME. Natural ligands accumulate in cells through the structural and rapid endocytosis of CD22. These ligands are classified and degraded in the lysosome, and CD22 is recycled back to the cell surface. In addition, CD22 ligand-induced endocytosis activates the intracellular pool, supplementing or increasing the expression level of CD22 on the cell surface. Therefore, CD22 has good endocytosis characteristics for ADC.

CD79b
CD79b is only expressed in immature and mature B cells, which is overexpressed in more than 80% of B cells in malignant tumors. CD79a and CD79b are two non-covalently bound transmembrane proteins that mediate signal transduction and endocytosis. For the latter, the CD79a-CD79b heterodimer is a scaffold that controls the endocytosis of BCR. The endocytosis of BCR is mainly completed by CME and mediated by AP-2. Interestingly, CD79a directly interacts with the μ subunit of AP-2, which in turn activates CD79b and leads to the endocytosis of the entire BCR complex.

In addition, as ADC, CD79a can be internalized as a monomer, but CD79b cannot. If the proximal membrane tyrosine (Y195) of CD79b mutates, the binding of AP-2 to CD79a will be blocked, and also the endocytosis. In 18% of activated B-cell-like DLBCL specimens, Y195 mutated. In summary, there is evidence that the endocytosis activity of CD79b depends on the internalization of the entire BCR complex rather than as a monomer.

HER2
HER2 is a 185kda transmembrane glycoprotein belonging to the EGFR family. The amplification of the HER2/neu gene is a known driver of human malignancies and metastasis, which therefore has been used as a therapeutic target for decades. HER2 has also been the target of ADCs, and both T-DM1 and T-DXT have been approved to treat patients with HER2-positive metastatic breast cancer.

There are multiple mechanisms of HER2 endocytosis. One is CME. Co-immunoprecipitation clearly shows that HER2 directly binds to AP-2. In addition, dynasore can completely block the HER2 endocytosis of SKBR3 cells. Secondly, caveolin binding motif φxφxxxxφ (φ stands for aromatic amino acids Trp, Phe, or Tyr) usually exist on caveolin-related proteins. Interestingly, the sequence WSYGVTIW has been identified in the intracellular kinase domain of HER2. In addition, studies showed that HER2 can utilize the endocytic pathway of CLIC/GEEC.

Analyzing the endocytosis of the target receptor and ADC can greatly promote preclinical research, clinical transformation, and patient treatment effects. Obviously, the efficiency of endocytosis is as important as the preferential overexpression status of ADC target receptors and other related parameters (such as PK).

The determination of the drug dose-exposure-effect relationship is a key part of a successful ADC. Therefore, endocytosis is very important for optimizing the dosing regimen to maximize the therapeutic index as the core of this relationship. Although the ADC field is currently in full swing, little is known about the endocytosis of the target receptor. In addition, many core components and key effectors of endocytosis are crucial. However, these proteins may commonly mutate in cancer, which will also affect ADC endocytosis and efficacy.
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Issued By www.creative-biolabs.com
Country United States
Categories Biotech
Last Updated October 15, 2021