List of various target antigens and cancers

The target antigen expression should be low or absent on the normal tissues, thereby limiting off-target effects. The antibody commonly used is immunoglobulin G related. Depending on the type of antibody, ADCs can be classified into three generations:[7]

• 1st generation – Chimeric antibody (e.g., brentuximab vedotin)

• 2nd generation – Humanized antibody (e.g., time-division multiplexing 1)

• 3rd generation – Fully human antibody (e.g., enfortumab vedotin).

The ideal antibody should have high binding affinity, target antigen specificity, nil or low immunogenic, nil or low cross-reaction, and good systemic retention.[8] Antibody is usually targeted at an antigen found only on target cells and that should not be downregulated on antibody binding. Recently, ADCs targeting the tumor microenvironment are undergoing clinical testing, which is beyond the conventional tumor-specific target strategy.[9]

Linker

The chemically engineered linker system forms the connection between the antibody and payload. The ideal properties of linkers are linker must be stable in the circulation so that ADC remains intact until it reaches target, conjugated inactively, nontoxic, and release the payload after the cellular internalization.[10] Unstable linker might lead to premature release of payload into the circulation, leading to systemic toxicities and very stable linker loses its effectiveness.

The linkers are broadly classified into cleavable and noncleavable depending on the cleavage by various factors.[11] Examples of cleavable linkers are enzymatic (sensitive to lysosomal proteases), acid labile (sensitive to an acidic pH), or disulfide (can be reduced by glutathione) and noncleavable linkers are thioether linker or hindered disulfide.[12]

Cleavable Linkers

Majority of the ADCs contain cleavable linkers. The main distinguishing feature is these are cleaved by various environmental factors such as pH, redox potential, and enzymatic reaction, for example, hydrolysis of acid-labile bonds, enzymatic cleavage of ester, or amide bonds. These mechanisms may occur within the lysosome/endosome compartments or cytosol. Lysosomal protease-sensitive and glutathione-sensitive disulfide linkers are the most commonly used linkers in ADC development. Other types of linkers are acid-labile linker and β-glucuronide linker.

Noncleavable Linker

Noncleavable linkers resist proteolytic degradation and exhibit greater stability than cleavable linkers. After cellular internalization of the ADC, within the lysosome, these linkers are degraded and the antibody is released. One of the drawbacks of noncleavable linkers is reduced efficacy due to impaired membrane permeability.

Payload/Warhead/Cytotoxic Moiety

The final and effector component of ADC is payload, which gets released into the cell, after release into the cytoplasm. The ideal payload properties are able to cause cell death even at low dose, stable in the circulation and lysosome, soluble in the aqueous solution, low immunogenicity, small molecular weight, long half-life, and conjugation friendly.[12] Payloads can be divided broadly into two groups: microtubule-disrupting agents and DNA-damaging agents. The list of payloads is given in [Figure 1].

Food and Drug Administration-approved list of antibody‑drug conjugates and their indication (till May 31, 2020)

Immunoconjugates and Radioimmunoconjugates

These are similar group of therapeutic agents where the cytotoxic agent is a toxin and radioisotope. An example of immunoconjugate is moxetumomab pasudotox, an anti-CD22 immunotoxin, in which an anti-CD22 antibody is fused to a toxin PE38 (pseudomonas exotoxin A). It was approved for the treatment of relapsed and refractory hairy cell leukemia. 90Y-Ibritumomab tiuxetan is a radioimmunoconjugate which is used in the treatment of non-Hodgkin lymphoma and the targeted antigen is CD20.

Acknowledgment

We sincerely acknowledge Dr. D Raghunadhrao for preparation of this manuscript.

Conflict of Interest

There are no conflicts of interest.

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Address for correspondence

Publication History

Received: 29 June 2020

Accepted: 19 August 2020

Article published online:
14 May 2021

© 2020. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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