22.5.3 MAb-Drug Conjugate

With an aim to antibody-mediated tumor-selective drug delivery, MAb-drug

conjugates have been developed. It relies on antibody-induced receptor internaliza-

tion, followed by trafficking of the MAb-drug conjugate to the lysosomes where the

cytotoxic drug is released, thereby initiating its antitumor activity. The linker joining

MAb and drug should be stable in the circulation to prevent premature release of the

cytotoxic drug. The most common linkers are either cleavable peptides by proteases

or disulfide linkers which undergo reduction in lysosomes to release the drug.

Brentuximab vedotin (trade name Adcetris^®) against CD30-positive Hodgkin’s

lymphoma and anaplastic large cell lymphoma has been approved for therapeutic

application. Another MAb-drug conjugate, trastuzumab emtansine (Kadcyla^®), has

also been used for metastatic breast tumors overexpressing HER2.

22.5.4 Fab Fragment and Other Formats of Therapeutic Antibodies

Ranibizumab (Lucentis^®) against VEGF for neovascular age-related macular degen-

eration has been expressed as Fab (comprising variable and constant domains of

light and heavy chains of antibody) fragment in E. coli (Ferrara et al. 2006). The

short half-life of Fabs can be increased by polyethylene glycol (Choy et al. 2002).

Sugar chain-modified antibodies (Ishida et al. 2012) and low molecular weight

antibodies (Ferrara et al. 2006) are also being explored as next-generation products.

Catalytic antibodies that not only recognize the target antigen but also degrade it

have been proposed as therapeutic agents. The catalytic antibody specifically

hydrolyzes the target antigen at the site recognized by it. Interestingly, catalytic

antibody reducing the β-amyloid accumulation in the brain of mouse has been

developed (Planque et al. 2015). Soluble cytokine receptors have been fused with

the antibody constant region and such biological are designated as “traps”. Trap

involving TNF receptor 2 fused with Fc (etanercept, Enbrel^®) has been approved to

treat rheumatoid arthritis. Other ligand “traps” approved are for IL-1 (rilonacept,

Arcalyst^®) and VEGF (aflibercept, Eylea^®) for retinopathy.

22.6

Potential of Therapeutic Human MAbs

Sixty-four MAbs have been approved by the US FDA up to 2018 for clinical use in

humans. It is projected that by 2022, expected sales of the therapeutic antibodies

may be around US$ 172.8 billion, which may constitute 20% of the global pharma-

ceutical market (Tsumoto et al. 2019). Fully human MAbs currently comprise more

than 55% of the market and constitute two-thirds of new MAbs approved by the US

FDA in 2017. In future, emerging economies such as China, Brazil, Russia, Turkey,

Mexico, South Korea, India, and Saudi Arabia will increase the market share of

therapeutic MAbs. To address competition from biosimilars, the use of MAbs for

newer clinical applications is being proposed. For example, Humira^®, the top selling

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S. K. Gupta and P. Chaudhary