For therapeutic applications of IL-6 antibodies see IL-6 under “immunology”

For cancer specific antibodies see the “cancer” section

Cancer and Lymphomas:

The first antibody for the treatment of cancer was a chimerica anti-CD20 for non-Hodgkin’s lymphoma. It was approved by the FDA in 1997 (Rituxan, from IDEC Pharmaceuticals Corproation and Genentech, Inc.) . Since the late 1990s, several other antibodies have been improved. Examples include antibodies for the treatment of breast cancer (Herceptin from Genentech). Some of the most important advances have been approval of bevacizumab (Avastin), an anti-vascular endothelial growth factor antibody, cetuximab (Erbitux), an anti-epidermal growth factor antibody and the anti-HER2/neu antibody trastuzumab (Herceptin) for breast cancer. (Adams, “Monoclonal antibody therapy of cancer” Nature Biotechnology, 23(9), 2005)

Anti HER2/nue (epidermal growth factor receptor 2)

EGFR (epidermal growth factor receptor 1)

VEGF (vascular endothelium growth factor):

–Aflibercept (brand name Eylea –Regeneron Pharmaceuticals): is used as an opthalmic agent to treat eye disores such as age-related macular degeenration. Ziv-alfibercept, sold under the brand name Zaltrap (Regeneron Pharmaceutica) was developed as an injection for treatment of metastatic colorecal cancer. Aflibercept is an assembly of two idential fusion polypetpide chains having the aflibercept amino acid sequence, typically produced by recombinant DNA expression technology. The two fusion polyptpide chains of aflibercept are covalently linked by disulfide linkage at amino acid positions 211 and 214. The fusion protein is typically glycosylated, with N-glycan covalently linked at asparagine resiudes at positions 36, 68, 123, 196 and 282. (EP3541365, dislcosing at least 99% aflibercept monomer and about 5% aggregate.).  

Aflibercept is a recombinant fusion prtoein that includes two main components: the vascular endothelia growth factor (VEGF) binding protions from extracellular domains of human VEGF receprots 1 and 2, fused to the Fc porition of human IgG1 (WO00/75319; US 7070959B2)

VEGF Trap is a soluble VEGF receptor that was engineered for therapeutic use and is curently approved by the FDA to treat AMD. The VEGF Trap contains the seocnd Ig-like domain 2 (D2) of VEGFR1 fused to the third Ig-like domain 3 (D3) of VERGF2 fused to the Fc region of human IgG1. VEGF Trap targets VEGF-A, VEGF-B and PIGF. The commercially available VEGF Trap is aflibercept (Eylea®, Regeneron). 

Insulin-like growth factor type 1 receptor (IGF-1R): is a tyrosine kinase receptor shown to be involved in tumorigenesis and several studies indicate that a number of tumors like breast, colon and osteosarcoma over express this receptor. Beck (J. Chromatography B, 819 (2005) 203-218) anti-IGF-1R antibodies

Non-Hodgkin Lymphoma: 

Anti-CD20: Rituxan® (Rituximab anti-human CD20, Genentech), is the first monoclonal antibody approved in the US to treat non-Hodgkin lymphoma. Rituximab (RITUXAN) is a genetically engineered chimeric murine/human mAb directed agaisnt the CD20 antigen. It is called “C2B8” in US 5,736,137, ussued April 7, 1998. It is indicated for the treatment of patients with relapsed or refractory low-grade or follicular CD20 positive B cell non-Hodgkin’s lymphoma.

There exists two different types of anti-CD20 antibodies differing significantly in their mode of CD20 binding and biological activities. Type I antibodies such as Rituximab, are potent in complement mediated cytotoxicity, whereas type II antibodies, such as Tositumomab (Bexxar®, B1) 11ß8 and AT80, effectively initiate target cell death via caspase-independent apoptosis with concomitant phosphatidylserine exposure (US 2009/0162352A1). 

Many studies indicate that complement-mediated cell death (CDC) play a critical role and also interacts synetergistically with Ab-dependent cell cytotoxicity in rituximab therapy. To further enhance CDC activity, the human IgG1 anti-CD20 mAb of alemtumzumabwas developed as another new mAb therapeutic.

Alemtuzumab has shown better activity for the treatment of relapsed chronic lymphocytic leukemia (CLL) compared to the activity associated with rituximab.

Despite these advances, about 50% of NHL patients are unresponsive to retuximab and some of the responsive patients develop resistance to further rituximab treatment. Since upregulation of human CD59 (hCD59) is an important determinant of sensitivity to Ab (rituximab and of a alemtuzumab) treatment for NHL and CLL, it is imperative to develop a molecule capable of abrogating CD59 function in cancer cells and facilitate Ab mediated cancer therapy. However, anti-hCD59 Abs have demonstrated unacceptable side effects and candidate competitive inhibitor peptides derived form C8 and C9 have also been ineffective.

You (Cellular & Molecular Immunolgoy (2011) 8, 157-163) developed a novel non-toxic and specific anti-hCD59 inhibitor: the domain 4 of intermediysin (ILY) which specifically abrogates hCD59 funciton in both normal human cells and B lymphoma cells and restored the sensitivity of a rituximab resistant NHL cell line to the rituximab CDC effect . 

Angiogenesis: 

Anti-VEGF

Vascular endothelia growth factor (VEGF) is a major mediator of angiogenesis associated with tumors and other pathological conditions. Presta (Cancer Research 57, 5493-5490, 1997) discloses that the murine anti human VEGF monoclonal angibody has been shown to suppress anglogenesis and growth in a varient of human tumor cells and described its humanization.

Avastin is a humanized IgG type I antibody to VEGF that blocks angioenesis. Angiogenesis, the growth of new blood vessels, is mediated by vacular endothelial growth factor (VEGF) and is the process by which tumors receive nutrients to grow larger.

Anemia: 

Anemia of chronic disease refers to any anemia that develops as a result of, for example, extended infection, inflammation and neoplastic disorders. The anemia which develops is often characterized by a shortened red blood cell life span and sequestration of iron in macrophages, which results in a decrease in the amount of iron available to make new red blood cells.

–Ferroportin 1 (FPN1) antibodies have been successfuly used in treating anemia. FPN1 is known to be a receptor for hepcidin, a polypeptide hormone made by the liver in response to iron stores. FPN1 is an iron transporting protein expressed in humans that has the ability to export cellular iron in response to interaction with hepcidin. Binding of mature hepcidin to FPN1 leads to the internalization and degradation of FPN1, preventing cellular iron export, and it is a major controlling factor of systemic iron hoemostasis.  WO2009/094551 and US 12/628263 describe FPN1 Mabs and methods of using them for treating disorders of iron homeostasis. By inhibiting the mature human hepcidin induced internalization and/or degreadation of human FPN1, one can increase transport of iron out of cells and elevate serum iron levels.

–Hepcidin antibodies: Hepcidin-neutralizing antiobides are therapeutically useful for treatment of disorders of iron homeostasis. Gately (US2009/0136495) teaches antibodies that bind to human hepcidin-25 which increase hemoglobin and/or hematrocrit, red blood cell count, reticulocyte count. Sasu (WO2008/097461) also teaches antibodies which bind human hepcidin and increase cirulating iron concentration. Sasu further teaches that antibodies may be screened for binding affinity by methods known in the art such as phage display technology or affinity maturation by panning methods.  For more on Hepcidin as a regulatory of iron see the vitamin iron.

Airway Diseases:

Anti-CD23:  IdEC-152 is an anti-CD23 antibody that inhibits IL-4 induced IgE production by B cells and is useful for treating IgE mediated pathologies such as atopic dermatitis, allergic rhinitis and asthma (US6,011,138). 

Inter-alpha-trypsin inhibitor (IaI) antibodies: 

Garantziotis (US13/133000) discloses administration of an antibody that specifically binds IaI to treat airway disords such as asthma, chronic obstructive pulmonary disease (COPD), cysitc fibrosis and airway hyperresponsiveness.

Breast Cancer (see “breast cancer” under “cancer”)

Castleman’s disease:

–Multicentric Casteman’s disease (MCD): is a rare disorder similar to lymphoma (cancer of the lumph nodes) which causes abnormal overgrowth of immune cells in lymph nodes and related tissues in the body. The disease usually affects adults who often suffer from fever, night sweats, weight loss and weakness or fatigue because their body’s immune system is compromised. Sylvant *siltuximab) is an FDA approved drug to treat patients with MCD. SYLVANT is an IL-6 antagonist indicated for the treatment of patients with MCD who are HIV negative and human herpesvirus-8 negative. It is marketed by Johnson & Johnson subsidiary Janssen Biotech and is the first drug backed by the FDA to treat MDC. 

Crohn’s disease: 

Adalimumab (HUMIRA, Abbott): binds to TNFalpha and was approved by the FDA in 2002 for the treatment of RA.   See also Remicade (Centocor, Inc) 

Arthritis

Rheumatoid arthritis:

–anti-TNF: 

Adalimumab (HUMIRA, Abbott) (also known as D2E7): binds to TNFalpha and was approved by the FDA in 2002 for the treatment of RA. Adalimumab is the first fully human (100% human peptide sequences) anti-TNFalpha monoclonal antibody which was engineered through guided selection techniques (phage display technology). It contains neither non-human components nor artificailly fused human peptide sequences. (Rau, Ann Rheum Dis 2002, 61).

Adalimumab, which delivers the same active substance as originator HUMIRA, is a fully human monoclonal immunoglobulin G1 antibody produced recombinantly in genetically engineered Chinese hamster ovary cells. Adalimumab is compoased of 1,330 amino acids with a MW of about 148 kDa. (Bandyopadhyay, Biosimilars, 2015: 1-18).

–Biosimilar adalimumab ZRC-3197 has been developed by Cardila Healthcare Ltd. Biosimilarity to adalimumab was shown with a comprehensive set of analytical techniques (Bandyopadhyay, Biosimilars, 2015: 1-18). 

Infliximab: is a chimeric (75% human and 25% mouse peptide sequences) anti-TNFalpha monoclonal antibody. Infliximab is given intravenously every two months and only in combination with methotrexate (Rau, Ann Rheum Dis 2002, 61).

Both infliximab and etanercept (p75 TNF-alpha receptor/immunoglobulin G fusion protein) are effective agaisnt rheumatoid arthritis, but only infliximab induces clinical remission in Crohn’s diease. (Mitoma, Gastroenterology 2005, 128: 376-392)

–CD20: Rituximab which is a chimeric mouse human monoclonal antibody agaisnt B cell specific antigen CD20 has been reported to be effective in cases of patients with RA. Depleting B cells using rituximab in patients with active SLE has also been shown to be beneeficial.

Juvenile Idiopathic Arthritis (JIA): 

Adalimumab (HUMIRA, Abbott): binds to TNFalpha and was approved by the FDA in 2002 for the treatment of JIA. 

Psoriatic Arthritis: Adalimumab (HUMIRA, Abbott): binds to TNFalpha and was approved by the FDA in 2002 for the treatment of psoriatic arthritis. 

Plaque Psoriasis: Adalimumab (HUMIRA, Abbott): binds to TNFalpha and was approved by the FDA in 2002 for the treatment of plaque psoriasis.

Infectious Diseases:

Respiratory Syncytial Virus Infections:

–Palivizumab: is a humanized monoclonal antibody *IgG1) used to prevent respiratory syncytial virus infections. 

Multiple Scelrosis:

–CD20:  Ocrelizumab is a humanized anti-CD20 mAb. It targets CD20 on B lymphocye and hence is an immunosuppressive drug candidate. It is FDA approved for MS and proprietary to Roche Holding (RHHBY)

Primary Sjogren’s Syndrome (TRIPSS):

–CD22:  Shirota (Oral Dis. 2008, 14(3)) states that targeting CD22 in systemic autoimmunity appears to be a potentially new therapeutic pathway and that clinical trials with epratuzumab which is a humanized anti-CD22 monoclonal antibody appears to be a promising therapy for patients with Primary Sjogren’s Syndrome (TRIPSS)  

Respiratory syncytial virus (RSV): Syangis (MedImmune, Inc) for respiratory syncytial virus (RSV) in children. 

Transplantation:

–Complement inhibitors: Lambris (WO2008/153962A2) discloses methods for reudcing rejection of pancreatic islet cells in the presence of a complement inhibitor, alone or combined with deextrane sulfate. Rother (WO2005/110481A2) also disclose methods of prolonging survival of allotransplanted cells, tissues or gains by adminsitering to the allotransplant recipient an inhibitor of complement activity together with one or more immunosuppressants. 

–anti-CD80:  IDEC-114 is an anti-CD80 MAb for treating autoimmune diseases and preventing organ tranplant rejection (US6,113,898). 

Ulcerative Colitis (UC):

Adalimumab (HUMIRA, Abbott): binds to TNFalpha and was approved by the FDA in 2002 for the treatment of UC.