Biology assignment on: Cetuximab
Cetuximab is a recombinant chimeric human murine immunoglobulin G1 antibody that binds to the extra-cellular domain of epidermalgrowth factor receptor with a higher affinity than either endogenous ligand. This binding inhibits receptor phosphorylation and activationand it leads to receptor internalization and degradation. Several studies have shown that cetuximab is able to inhibit growth of epidermalgrowth factor receptor (EGFR)-expressing tumour cells in vitro. Moreover, treatment with cetuximab results in a marked inhibition of tumourgrowth in nude mice bearing xenografts of human cancer cell lines. These results are linked to cetuximab biological effects as inhibition ofcell cycle, tumour progression, neo-angiogenesis, invasion and metastatization, as well as increase and activation of pro-apoptotic molecules.Additionally, cetuximab potentiates, in combination, the effects of chemotherapy and radiation therapy in eradicating well-established tumoursin nude mice and it may even reverse the resistance to some cytotoxic agents in these xenografts.Moreover, numerous clinical trials demonstrated cetuximab efficacy in different tumour types. It has been approved by Food and DrugsAdministration in the treatment of metastatic colorectal cancer as single agent or in combination with chemotherapy, in locally and regionally (Bruno Vincenzi, 2008)
HERsare cell membrane-bound glycoproteins, comprising 4 distinctreceptors: EGFR, also known as HER1; HER2; HER3; andHER4.2,7,8 These receptors are divided into 3 regions: an extracellularligand-binding region, an intracellular region with tyrosinekinase activity, and a region that spans the cell membraneand anchors the receptor to the cell. Ligand binding to the extracellulardomain promotes formation of dimers, homodimersbetween monomers of same receptor), or heterodimers (betweenthe bound receptor and other members of the HER family),activating tyrosine kinase, triggering a cascade of complexcell biochemistry that regulates various cell functions, such as cellproliferation, angiogenesis, apoptosis, adhesion, and motility(W. Bou-Assaly, 2010).
Cetuximab, a monoclonal antibody, binds to the extracellulardomain of the EGFR, which is overexpressed in manyhuman cancers, including head and neck and colorectal types.This process prevents the EGFR from binding with its endogenousligand, blocking the receptor-dependent transductionpathway and providing many antitumor effects, involvingcell-cycle arrest, induction of apoptosis, inhibition of angiogenesis,inhibition of metastasis, internalization and downregulationof the EGFR, and enhancement of the sensitivity toradiochemotherapy (W. Bou-Assaly, 2010).In the EU and the US, cetuximab has beenapproved for use with concomitant radiotherapy in patients with locally advancedsquamous cell carcinoma of the head and neck (SCCHN) and in combination withirinotecan for the treatment of metastatic colorectal cancer (mCRC) in patientswith EGFR-expressing tumours who are refractory to irinotecan-based therapy. Inthe US, cetuximab has also been approved as monotherapy in patients withrecurrent or metastatic SCCHN for whom platinum-based therapy has failed andin patients with mCRC who are intolerant of irinotecan-based regimens(Stephanie K.A., 2007)
Panitumumab (formerly known as ABXEGF)is a high-affinity fully human immunoglobulin G2 anti-EGFR monoclonal antibody. Panitumumab binds to theectodomain of the EGFR with high affinity, preventing it frombinding with its natural ligands. In in vitro models, panitumumabhas shown inhibition of EGFR tyrosine phosphorylationand cell proliferation. In vivo, panitumumab completelyprevented the formation of human epidermoid carcinomaA431 xenografts in athymic mice, resulting in completeeradication of established tumors. This effect has also beenobserved in human pancreatic, renal, breast and prostate tumorxenografts. Panitumumab is being extensivelyevaluated in metastatic colorectal cancer(JosepTabernero, 2007).
Erlotinib and Gefitinib are a small-molecule quinazolinamine and anilinoquinazoline, respectively, thatreversibly inhibits the EGFR tyrosine kinase and prevents receptor autophosphorylation. Erlotinib is approvedin the United States, Europe, and several other countries asmonotherapy for the treatment of patients with locally advancedor metastatic NSCLC after failure of at least one prior chemotherapyregimen(JosepTabernero, 2007).
VEGF is secreted by tumor cells in the majority of cancers andacts on endothelial cells of existing blood vessels to promotenew blood vessel formation. VEGF release by tumor cellsinitiates the angiogenic process by activating endothelial cellsand promoting their migration and, thus, induces the angiogenicswitch(JosepTabernero, 2007).
Bevacizumab is a recombinant humanizedimmunoglobulin G1 monoclonal antibody that binds to VEGFand inhibits its activity, thereby inhibiting angiogenesis andpotentially halting tumor growth (36, 52). Bevacizumab iswidely approved for use in combination with 5-fluorouracil(5-FU)– and irinotecan-based chemotherapy regimens forthe first-line treatment of metastatic colorectal cancer(JosepTabernero, 2007).
Sunitinib malate (SU11248) is an orallyactive inhibitor of protein tyrosine kinases, which has activityagainst VEGF receptors 1, 2, and 3; PDGF receptors alpha and beta; c-Kit; and Flt-3 tyrosine kinase receptors.(JosepTabernero, 2007).
Vatalanib is a receptor tyrosine kinase inhibitorwith activity against VEGF receptors 1, 2, and 3; PDGFreceptor; c-Kit; and c-Fms(JosepTabernero, 2007).
One of the most intriguing developments in anti-EGFRtherapy has been elucidation of the role of KRAS mutationas a predictive biomarker. KRAS is a small serine-threoninekinase that is farnesylated and inserted into the cellmembrane. It is activated just downstream of EGFR andpropagates further signaling events. Mutations occur atcodons 12, 13, and 61, and they cause constitutiveactivation of KRAS. Both retrospective and prospectivestudies analyzing KRAS mutations have shown that anti-EGFR therapy is ineffective in patients with tumors thatharbor KRAS mutations. Thus, anti-EGFR therapy is only recommended for patients with KRAS wild-type tumors.Anti-EGFR Therapy in the Metastatic SettingIn the metastatic CRC setting, there is evidence that somepatients with KRAS wild-type tumors benefit from theaddition of anti-EGFR monoclonal antibody therapy tochemotherapy. The two clinically employed anti-EGFRagents are cetuximab, a mouse-human chimeric anti-EGFR IgG1 antibody, and panitumumab, a fully humanizedanti-EGFR IgG2 antibody. They appear to have similarclinical activity, although cetuximab possesses the additionalanti-tumor mechanism of antibody-dependent cellularcytotoxicity (ADCC) because its specific Fc structureimparts an ability to engage Fc receptor (FcR)–basedimmune effector responses.Anti-EGFR therapy and KRAS status has been studiedin three phase 3 trials for treatment of metastatic CRC inthe first-line setting. The CRYSTAL trial compared 5-FUand irinotecan (FOLFIRI) to FOLFIRI and cetuximab.There was an improvement in overall survival (OS) from 20to 23.5 months, as well PFS from 8.4 to 9.9 months withthe addition of cetuximab to FOLFIRI in patients withKRAS wild-type tumors [4]. The COIN trial randomizedpatients to three arms: continuous 5-FU and oxaliplatintherapy; continuous 5-FU, oxaliplatin, and cetuximabtherapy; and intermittent 5-FU and oxaliplatin therapy.
Recently, antibody-based anticancer therapies that involvesmaller antibody fragments such as Fabs, ScFvs and nanobodies have been emerging . Nanobodies are derived from heavychain-only antibodies found in camelids (e.g., Llama glama) andconsist solely of the antigen-specific domain (VHH) . Thesesingle-domain antibodies are significantly smaller in size (15kDa) than scFv (28 kDa) or Fab (55 kDa), thereby potentiallyproviding higher tissue dispersion than their counterparts . Inaddition, nanobodies are significantly more stable than VHdomains and have improved penetration against immune-evasive(cryptic) antigens compared with mAbs (10, 11). Nanobodiesspecific for EGFR have recently been developed and shown to be able to sterically hinder the binding of EGF to the receptor,thereby inhibiting EGFR signalling(Jeroen A., 2012)
For accurate diagnosis of tumors and tumor locations, strongimaging tools with high specificity are essential. Antibodies directedagainst tumor-specific epitopes have been shown to have great potential for tumor imaging (29). Recently, the potential ofmonovalent anti-EGFR nanobodies for tumor imaging usingsingle-photon emission computed tomography(SPECT) was examined and it was shown that the nanobodieshome to EGFR-overexpressing tumors. So, anti-EGFR nanobodiesare good candidates for diagnostics and tumor localization (Jeroen A., 2012).
The CSC hypothesis, as enticing as it sounds, still carries many controversies. There is considerable evidence for their existence, across a range of tumor types; yet a major stumbling block has been the ongoing challenge of successful isolation of this putative stem cell subpopulation from their natural milieu and the ability to control their behaviour. However, there has been impressive progress in our quest to identify and characterize the intestinal stem cell, so perhaps the search to accurately define this fascinating subpopulation is not too far in the future. The CSC theory has significant clinical and therapeutic implications. The use of chemotherapy may well be streamlined by the future option of subtyping tumors to identify the putative stem(Jawad& Wright, 2012)
indisulam and CPT-11 administered incombination demonstrated synergistic interaction both invitro and in vivo with a rationalized mechanism. There wasno overlap in toxicities between indisulam and CPT-11.There was no metabolic drug–drug interaction betweenindisulam and CPT-11 in mice. These Wndings suggest thatthe combination of indisulam and CPT-11 is promising forcancer therapy. Clinical studies of this combination are ongoing(Yoichi Ozawa, 2012).
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