MAbs therapy approval

Currently, 28-30 mAbs are approved, or under consideration for approval, as specific therapies in the USA or European Union, although about 350 new mAbs for therapeutic appheation in humans are in the commercial pipeline. 

The ground-breaking development of monoclonal antibodies by Kohler and Milstein [21] initiated the development of antibody-mediated therapeutics for cancer. Because of their unique specificity, MAb were predicted to become the magic bullets in the battle against cancer. Over the last two and a half decades MAbs have moved from clone to clinic for the treatment of various malignancies. Several MAbs are currently entering clinical trials and should appear on the market in the next few years. The first MAb for cancer therapy was approved in the US in 1997. 

As of 2008, 25 therapeutic monoclonal antibodies (mAbs) mAbs had been approved for clinical use in the United States, and with over 400 antibodies being in preclinical and clinical development further increase of antibody therapies is assured (10, 11). As a general rule, the Fc fragment is a key component of therapeutic mAb design because it extends their pharmacokinetics. Inclusion of the Fc from IgG is also a key component of other bioactive proteins where prolongation of pharmacokinetics is desired, e.g., the tumor necrosis factor receptor (TNFR) fusion protein etan-ercept (Enbrel ) (12). Thus for both therapeutic antibodies and Fc-fusion proteins, the FcRn interaction is a generalized way to exploit FcRn protection to achieve the benefits of extended persistence in vivo. 

The first therapeutic antibody approved (Orthoclone OKT-3 or Muromonab CD3, 1986) was indicated not for cancer treatment, but for controlling acute rejection of transplanted organs (kidney, heart, and liver). Nowadays, other clinical indications such as asthma, rheumatoid arthritis, psoriasis, and Crohn s disease are treated with mAbs (see Chapter 17) (Antibody Engineering and Manufacture, 2005 Monoclonal Antibodies and Therapies, 2004 Hot Drugs, 2004 Walsh, 2004). 

Infliximab (in FLICKS ih mab) is a chimeric IgGic monoclonal antibody composed of human and murine regions. The antibody binds specifically to human TNF-a, thereby neutralizing that cytokine. Infliximab has been approved for Crohn s disease for both fistulizing and non-fistula disease. [Note Increased levels of TNF-a are found in fecal samples of patients with Crohn s disease.] It is not approved for maintenance therapy beyond six weeks. Approval for the treatment of rheumatic arthritis in combination with methotrexate is anticipated in the near future. 

I Biologic Therapy. Bevacizumab (Avastin, rhu-MAb VEGF) is a recombinant, humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). Bevacizumab, in combination with intravenous fluorouracil-based chemotherapy, was approved by the FDA in 2004 for initial treatment of patients with... 

We believe that the increasing numbers of US market approvals of monoclonal antibodies (mAbs) and recombinant therapeutic proteins for the US market will encourage biotech firms to pursue novel therapies for an increasing number of indications. Eurthermore, sequencing of the human genome provides multiple new tar-... 

Induction therapy with polyclonal and monoclonal antibodies (mAbs) has been an important component of inunu-nosupression when the beneficial effect of antilymphocyte globulin (ALG) in the prophylaxis of rejection in renal transplant recipients was demonstrated. Over the past 40 years, several polycolonal antilymphocyte preparations have been used in renal transplantation however, only two preparations are currently FDA approved lymphocyte immune globulin (ATGAM) and antithymocyte globulin (Thymoglobulin). 

Over the past decade, a wide variety of antibody-based targeting molecules have been assessed for their potential application in cancer therapy [200]. Monoclonal antibodies (mAb) were the first and are still the preferred class of targeting molecules. Current developments of antibodies have been focused on chimeric, humanized, and fully humanized derivatives to decrease their immunogenicity. Some of these antibody-based drugs have already undergone clinical development and have been successfully translated into the clinical environment. Such examples include rituximab (Rituxan ), trastuzumab (Herceptin ), cetuximab (Erbitux ), and bevacizumab (Avastin ). Rituximab was approved by the FDA for treating B-cell lymphoma in 1997. 

Skin Paradoxically, anti-TNFu therapies have been implicated in the development, or worsening, of psoriasis [151 219, 220, 221, ] and it seems that ustekimunab which is approved for the treatment of psoriasis and has been used to treat anti-TNFu-induced psoriasis [221 222, ] may also sometimes show this effect. For example, two patients developed psoriatic arthritis during treatment with ustekinumab for psoriasis [223 ] and the mAb has been found to induce/Zflres cf psoriatic arthritis [224 ] and pustular psoriasis [225 ]. 

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