See also therapeutic applications of antibodies   See also Antibodies as toxic drug carriers in drug delivery. 

Companies:  Immunogen 

 Often membrane-associated polypeptides are specifically expressed on the surface of one or more particular type(s) of cancer cell as compared to on one or more normal non-cancerous cell(s). Often, such polypeptides are more abundantly expressed on the surface of cancer cells. The identification of such tumor associated cell surface antigen polypeptides has given rise to the ability to specifically target cancer cells for destruction via antibody based therapies. About 70 humanized monoclonal antibodies (mAbs) against tumor antigens are currently in human clinical trails, and 3 mAbs, Rituximab, herceptin and Alemtuzumab have been approved by the FDA. Such antibodies may also be conjugated to a toxin which can kill the tumor cell. 

Such tumor antigens include receptors of the erbB class such as EGFR, HER2-4, insulin growth factor recetpor I (IGF-RI), c-met, receptors of the tumor necrosis factor family such as DR4-5, DcR1, DCR2, IL-17 recetpor, IL-23 receptor, IL-12 receptor and interferon-alpha receptor (EP2546268).

The mere binding of antibodies to cells does not always lead to their destruction. Thus, attempts have been made to render antibodies cytotoxic by attaching a drug, toxin or radiolabelled isotope to them, so called “magic bullets”. (Segal US 4,676,980) See Drug Delivery

Mechanism of Action

A major antitumor mechanisms of mAbs is thought to be by antibody-dependent cellular cytotoxicity (ADCC). mABs specific for tumor cell surface antigens bind to the tumor cell through their antigen binding domains and, through the Fc region of the mAb, bind to cells such as NK cells and neutrophils that express Fc receptors. This binding event is thought to activate the FcR-expressing cell, which results in ADCC. Most antibodies that mediate ADCC can also cause CDC. However, CDC does not play a big role in the mAb mediated destruction of tumor cells, as these cells tend to overexpress complement regulatoyr proteins (e.g., CD46, CD55, CD59). Interference with the function of these proteins may promote CDC. Therapetic anti-cancer mAbs may also induce apoptosis of cancer cells by blocking binding of growth factors to their receptors and/or sensitive cancer cells to chemotherapy and radiotherapy as well as act as anti-angiogenic agents by blocking the binding of VEGF to its receptor. Therapeutic may also block intracellular signaling pathways. Ionnello (Cancer and Metastusis Reviews 24: 487-499, 2005). For example, bevacizumab binds to the soluble VEGF and thus inhibits angiogenesis, which is important for maintenance of tumor vaculature and tumor health. Goswami (Antibodies 2031, 2, 452-500)

Tumor Antigens and Antibodies which Target These Antigens

B7H4: Terret (WO2009/073533) discloses B7H4 antibodies which are useful for treating cancer. B6-H4 exerts its physiologic function by binding to a receptor on T cells, which in turn induces cell cycle arrest and inhibits the secretion of cytokines, the development of cytotoxicity and cytokine production of CD4+ and CD8+ T cells. Chen (US2008/026235) also discloses administering an effective amount of a B7-H4 antagonist such as an antibody which can be used to enhance an immune response to treat cancer. 

CALLA: The monoclonal antibody J5 is specific for Common Acute Lymphoblastic Leukemia Antigen (CALLA) and can be used to target cells that express CALLA (e.g., acute lymphoblastic leukemia cells).

c-Met: is the cell surface receptor for hepatocyte growth factor (HGF), also known as scatter factor. The c-Met receptor is a disulfide linked heterodimer consisting of extracellular alpha and beta chains. The alpha chain, heterodimerized to the amino terminal portion of the beta chain, forms the major ligand binding stie in the extra cellular domain. HGF binding induces c-Met receptor homodimerization and phosphorylation of two tyrosine residues within the catalytic site, regulating kinase activity. HGF mediated activation of c-Met results in a complex genetic program referred to as invasive growth, consisting of a series of physiological processes, including profliferation, invasion, and angiogenesis that occur under normal physiological conditions during embryonic developmetn and pathologically during oncogenesis. In tumour cells, c-Met activation causes the triggering of a diverse series of signalling cascades resulting in cell growth, proliferation, invasion and protection from apoptosis.

A variety of c-Met pathway antagonists such as monoclonal antibodies with potential clinical applications are currently under clinical investigation. Examples include the anti-c-Met 5D5 antibody generated by Genentech (WO96/38557). WO2009/007427 also describes mosue monoclonal antibodies to c-Met and chimeric variants in which the antigen binding domains of the mosue monoclonal antibody are coupled to the constant region of human IgG1.

Hultberg 9US2012/0156206) discloses a combination of antibodies binding to the human c-Met protein and more specifically combinations of two or more c-Met antibodies which bind to distinct, non-overlapping epitopes. Such antibodies have advantageous properties in that the combinations can produce potent inhibition of HGF independent activaiton of the human c-Met receptor.

CD4: An anti-CD4 Mab that is useful for T cell depletion therapy is IDEC-151 (US 6,136,310). 

CD20: In 1997, the FDA approved RITUXAN® (IDEC Pharmaceuticals Corp. and Genetechn, Inc.,) (also referred to as rituximab), a chimeric anti-CD20 antibody for the treatment of non-Hodgkin’s lymphoma.

Rituximab is a mAb consisting of a human kappa constant region, a human IgG Fc portion and a murine variable region. The exact antitumor mechanisms of rituximab remains unclear, but it is assumed that it exerts its effects by various mechanisms including activaiton of complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC) and signaling of apoptosis by binding to the CD20 antigen specifically expressed on B cells. Although most patients with B cell non-Hodgkin lymphoma respond to initial rituximab treatment, a significant number become unresponsive. It has been shown that complement regulatory proteins such as CD55 and CD59 are associated with acquisition of resistance. (K. Takei, Leukemia Research 30 (2006) 625-631. 

CD22: is a 140 kDa member of the Siglec family of cell surface proteins that is expressed by most mature B cell lineages. . It is also a member of the sialadhesin family of adhesion molecules that includes sialoadhesin and myelin-associated glycoprotein. Sialoadhesin and CD22 mediate cellular interactions by recognizing sepcific cell surface sialylated glycoconjugates. Remarkably, mAbs which blocked CD22 ligand binding were shown to accelerate mature B cell turnover and inhibit the survival of adoptively transferred normal and malignant B cells in vivo. In addition, mAbs that boudn CD22 ligan binding domains induced significant CD22 internalization, depleted marginal zone B cells and reducd mature recirculating B cell numbers by 75-85% in the mouse (Haas, J Immunol. 2006, 177(5): 3063-73). 

CD22 is an attractive molecular target because of its restricted expression. It is not exposed on embvyonic stem cells but is highly expressed on B cells in NHL. A murine anti-CD22 mAb has been developed for imaging and treatment of NHL. Anti-CD22 antiboides also have potential as carriers of cytotoxic agents since they rapidly internalise and human CD22 has been trageted using mAb conjugates linked to toxins such as derivatives of Pseudomonas exotoxin. A particularly exciting possibility is using CD22 targetted RNAses. This has the advantage of overcoming limitations experienced in using toxins. RNAses are not immunogenic in animal studies nor does a naked RNAse cause immunological problems in humans (newton, Expert Opin. biol. Ther: (2001) 1(6): 995-1003).

Jones (US 8,389,688) discloses humanized versions of anti-CD22 mouse mAbs which can be used in the treatment of B cell malignancies.

Epratuzumab is a humanized antihuman CD22 IgG1 antibody which has shown promising clinical activity both as a single agent and in combination with rituximab in patients with non-Hodkin’s lymphomas (NHL) Wang, Clin Cancer Res. 2003, 9 (10 Pt2): 3982S-90S

CD33: The monoclona antibody MY9 is a murine IgG1 antibody that binds specifically to the CD33 antigen and be used to target cells that express CD33 (e.g., acute myelogenous leukemia (AML) cells. 

CD88: IDEC-114 is an anti-CD80 MAb for treating autoimmune diseases and preventing organ transplant rejection (US 6,113,898). 

CD200: Bowdish (WO2007/084321) discloses anti CD200 anitobides for treatment of cancer. 

EGFR: Aberrant expression of epidermal growth factor receptor (EGFR) has been observed in a variety of solid tumors, and often correlates with a poor clinical outcome for patients. These features make EGFR an important target for cancer therapeutis, linke mAbs and tyrosine kinase inhibitors (TKI). Anti-EGFR mAbs paneitumumab (Vectibix) and cetuximab (Erbitux) are established agents in the treatment of colorectal cancer. Yang, “Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency” mAbs (2015). 

IGF-IR (type 1 insuline-like growth factor receptor): has been implicated in promoting oncogenic transformation, growth and survival of cancer cells. WO20007/110339 discloses antibodies that bind to the extracellular domains of IGF-IR and inhibit receptor activation. 

VEGF (Human vascular endothelial growth factor): VEGF is involved in the regulation of normal and abnormal angiogenesis and neovascularization associated with tumors as well as intracoular disorders. VEGF is a homodimeric glycoprotein that has been isolated from several sources. It shows highly specific mitogenic activity for endothelial cells. It ahs important regulatory functions in the formation of new blood vessels during embryonic vasculogenesis and in angiogenesis during adult life. Anti-VEGF nuetralizing antibodies suppress the growth of a variety of human tumor cell lines in mice. WO 94/10202, WO 98/45332, WO 2005/00900 and WO 00/35956 refers to antibodies against VEGF.

Humanized monoclonal antibody bevacizumab (sold under the trade name Avastin) is an anti-VEGF antibody used in tumor therpay (WO 98/45331).

Ranibizumab (trade name Lucentis) is a monoclonal antibody fragment derived form the same parent murine antiboy as bevacizumab. It is much smaller than the parent and has been affinity matured to provide stronger binding to VEGF-A (WO 98/45331). It is an anti-angiogenic that has been approved to treat the “wet” type of age-related macular degneration, a common form of age related vision loss. 

Another anti-VEGF antiboy HuMab G6-31 is described in US 2007/0141065. 

ANG-1/ANG-2 (Human angiopoietin-2): ANG-1 and ANG-2 were discovered as ligands for the Iites, a family of tyrosine kinases that is selectively expressed within the vascular endothelium. Corneal angioenesis assay have shown that both ANG-1 and ANG-2 had similar effects, acting syntergistically with VEGF to promote growth of new blood vessels. 

WO2011/117329 discloses a bispecific, bivalent antibody that includes a first antigen bidning site for human VEGF and a second antigen binding ste for human ANG-2. 

Histones: It has been shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during spesis. Esmon (US2009/0117099) discloses that inhibitors of histones such as antiboides that bind to H1, H2A, H2B, H3 and H4 can also be used to alleviate toxicity in cancer cuased by chemotherapy, radiation and cytokines.  Svanborg (US2006/0233807) also disclsoes using a moeity which specifically binds to hisone such as an antibody such that the chromatin assembly or remodeling activity of the cell is inhibited. The method is disclosed as being useful for the treatment of cancer. 

Antigens which are Overesxpressed in Certain Types of Cancers and Monoclonal Antibodies which Target these antigens

Claudin-18.2: is overexpressed in up to 80% of gastrointestinal adenocarcinomas and 60% of pancreatic tumors, in addition to other solide cancers. Astellas has a monoclonal candicate IMAB362 that targets this tight junction protein.

Antibodies against Immune check point proteins

Immuen checkpoint proteins are a set of proteins that act as either stimulators or inhibitors of the immune system. By dampening or attenuating the “off-switch” an immune response is enhanced. The most well known checkpoint targets are the following:

cytotoxic T lymphocyte-assocaited antigen 4 (CTLA-4):  ipilimumab is an anti-CTLA-4 soled as Yervoy by Bristol-Myers Squibb. (WO2016063263) discloses that the bacterium Bacteroides fragilis improved the antitumor efficacy of an anti-CTLA-4 antibody. 

programmed cell death 1 (PD-1):  Pembrolizumab is an anti-PD-1 sold as Keytruda by Merck

programmed death ligand 1 (PD-L1). nivolumab is sold as Opdivo by Bristol-Myers Squibb.  (US20150352206) discloses that Bifodobacterium improved the antitumor efficacy of an anti-PD-L1 antibody in a mouse model of melanoma. 

T cell receptor therapeutics:

TCR arm – antibody domain; TCR like antibodies:

As part of normal immune surveillance, intracellular.proteins are degraded by the proteasome into short peptide fragments of about 8-10 amino acids which are presented on the cell surface bound to MHC molecules, known as human leukocyte antigen (HLA) molecules in humans. Circulating T cells bind specific peptide MHC complexes with their TCRs, continuously monitoring for intracellular ref flags that are processed and displayed on the cell surface. Immunocor’s tebentafusp is approved by the FDA for uveal melanoma. The bispecific biologic molecules combines a TCR arm that recognizes tumour cells with an antibody domain to bind and activate T cells. For tebentafusp, Immunocore uses a TCR domain to recognize an epitope of gp100, a transmembrane glycoprotein that is located on the ER and epxressed in melanocytes and melanoma –as presented on HLA-A*02:01. The T cell engaing arom fo the bispecifiv binds CD3on T cells. For this therapy, one just needs ti know gp100 (a tumor specific antigen) and the patien’ts HLA. (Nature Reviews Drug Discovery, 21, May 2022, 321). 

Roche has made it into the clinic with a TCR mimicking bespecific called RG6007. One antibody domain recognizes a fragment of the cancer associated transcription factor WTI presented on HLA-A&*02 and the other binds CD3 on T cells. (Nature Reviews Drug Discovery, 21, May 2022, 321)

HLA restriction poses one challenge for TCR based approaches. There are multiple HLA genes, and each has numerous variants. But first generation TCR therapies can only bind theri targets in patients harbouring a certain HLA allele. Some alleles are more common in particular populations, providing starting points for frug developers. Tebentafusp, for example, takes aim at the HLA-A*02 subtype, which is present in about 40% of the global population and over 95% of white populations. But patients with other subtypes will need different therapeutics. A greater challenge for teh field is choosing the best TCR target. Finding a protein expressed exclusively in tumour cells is just the begninng, as MHC presentation of the peptidome is a complex and dynamic process. (Nature Reviews Drug Discovery, 21, May 2022, 321)

T cell redirecting antibody (TRAB):

Antibodies which bind a tumor cell specific antigen on one arm and CD3 on a T cell by the other arm thereby inducing cytotoxicity against the tumor cell by bridging the tumor cell and the T cell have been developed. (“Proprietary Innovative antibody engineering technologies in Chugai Pharmaceutical”, 12/18/2012).