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Current ADC Linker Chemistry.

Jain N, Smith SW, Ghone S, Tomczuk B - Pharm. Res. (2015)

Bottom Line: Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation.These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine.This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.

View Article: PubMed Central - PubMed

Affiliation: The Chemistry Research Solution, LLC, 360 George Patterson Blvd., Suite 101E, Bristol, Pennsylvania, 19007, USA. njain@tcrs-us.com.

ABSTRACT
The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.

No MeSH data available.


Related in: MedlinePlus

Mechanism of action of ADCs: The antibody portion of an ADC hones onto a cell-surface antigen that is ideally specific to a cancer cell. Upon binding, the ADC-antigen protein complex becomes internalized into the cancer cell. When the complex is degraded, it releases the cytotoxin which then binds to its target to cause cancer cell apoptosis.
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Fig2: Mechanism of action of ADCs: The antibody portion of an ADC hones onto a cell-surface antigen that is ideally specific to a cancer cell. Upon binding, the ADC-antigen protein complex becomes internalized into the cancer cell. When the complex is degraded, it releases the cytotoxin which then binds to its target to cause cancer cell apoptosis.

Mentions: The mechanism of action of a successful ADC is depicted in Fig. 2. After being introduced into the plasma (step 1), the ADC recognizes an antigen on the cell surface (step 2). The ADC-antigen complex then undergoes endocytosis, termed internalization (step 3). Once inside the tumor cell, the ADC-antigen complex is fused with the endosome which breaks up the complex for antigen recycling and transports the ADC to the lysosome. Finally, the ADC undergoes various lysosomal degradations to release the cytotoxic drug (step 4), which then binds to its target. The majority of payloads cause cell death or apoptosis via either DNA intercalation or through binding to microtubulins (step 5). Thus, the ideal tumor antigen must be localized on the cell surface in order to allow efficient ADC binding. In addition, the antigen should demonstrate restricted expression on tumor cells, i.e., the antigen should be predominately expressed on tumor cells with minimal expression on normal cells. An important factor for the therapeutic index is the antigen density since a small number of antigenic sites would pose a problem for efficient ADC targeting, internalization and delivery. It has been estimated that the delivery of a lethal quantity of a tubulin-acting payload into a tumor cell may be difficult to achieve below ~10,000 antigen proteins per cell (2). For the antibody, it must be able to bind to tumor-associated antigens with high specificity and high affinity. In addition, the antibody should be non-immunogenic, an issue that has been minimized with chimeric and fully-humanized monoclonal antibodies (3). The ideal payload, or cytotoxin, needs to have high potency against the specific tumor type since it has been estimated that only 1–2% of the administered drug reached the intracellular target (e.g., tumoral DNA or microtubules) (4). The tubulin-binding cytotoxins, such as the maytansinoids or the auristatins, have in vitro cytotoxic potencies in the picomolar range (10−12 M). What has become clear is that every component of an ADC must be optimized in order to fully realize the goal of a targeted therapy with improved efficacy and tolerability.Fig. 2


Current ADC Linker Chemistry.

Jain N, Smith SW, Ghone S, Tomczuk B - Pharm. Res. (2015)

Mechanism of action of ADCs: The antibody portion of an ADC hones onto a cell-surface antigen that is ideally specific to a cancer cell. Upon binding, the ADC-antigen protein complex becomes internalized into the cancer cell. When the complex is degraded, it releases the cytotoxin which then binds to its target to cause cancer cell apoptosis.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4596905&req=5

Fig2: Mechanism of action of ADCs: The antibody portion of an ADC hones onto a cell-surface antigen that is ideally specific to a cancer cell. Upon binding, the ADC-antigen protein complex becomes internalized into the cancer cell. When the complex is degraded, it releases the cytotoxin which then binds to its target to cause cancer cell apoptosis.
Mentions: The mechanism of action of a successful ADC is depicted in Fig. 2. After being introduced into the plasma (step 1), the ADC recognizes an antigen on the cell surface (step 2). The ADC-antigen complex then undergoes endocytosis, termed internalization (step 3). Once inside the tumor cell, the ADC-antigen complex is fused with the endosome which breaks up the complex for antigen recycling and transports the ADC to the lysosome. Finally, the ADC undergoes various lysosomal degradations to release the cytotoxic drug (step 4), which then binds to its target. The majority of payloads cause cell death or apoptosis via either DNA intercalation or through binding to microtubulins (step 5). Thus, the ideal tumor antigen must be localized on the cell surface in order to allow efficient ADC binding. In addition, the antigen should demonstrate restricted expression on tumor cells, i.e., the antigen should be predominately expressed on tumor cells with minimal expression on normal cells. An important factor for the therapeutic index is the antigen density since a small number of antigenic sites would pose a problem for efficient ADC targeting, internalization and delivery. It has been estimated that the delivery of a lethal quantity of a tubulin-acting payload into a tumor cell may be difficult to achieve below ~10,000 antigen proteins per cell (2). For the antibody, it must be able to bind to tumor-associated antigens with high specificity and high affinity. In addition, the antibody should be non-immunogenic, an issue that has been minimized with chimeric and fully-humanized monoclonal antibodies (3). The ideal payload, or cytotoxin, needs to have high potency against the specific tumor type since it has been estimated that only 1–2% of the administered drug reached the intracellular target (e.g., tumoral DNA or microtubules) (4). The tubulin-binding cytotoxins, such as the maytansinoids or the auristatins, have in vitro cytotoxic potencies in the picomolar range (10−12 M). What has become clear is that every component of an ADC must be optimized in order to fully realize the goal of a targeted therapy with improved efficacy and tolerability.Fig. 2

Bottom Line: Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation.These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine.This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.

View Article: PubMed Central - PubMed

Affiliation: The Chemistry Research Solution, LLC, 360 George Patterson Blvd., Suite 101E, Bristol, Pennsylvania, 19007, USA. njain@tcrs-us.com.

ABSTRACT
The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.

No MeSH data available.


Related in: MedlinePlus