Skip to Main contentScienceDirectJournals BooksRegisterSign in Sign inRegisterJournals BooksHelpBispecific Monoclonal AntibodyBispecific monoclonal antibodies contain two antibodies with specificity for distinct targets [27] and are thus able to directly conjugate the immunological effector cells and the tumor cells.From: Gene Therapy of Cancer (Second Edition), 2002Related terms:T CellNatural Killer CellT CellsCytokineTrastuzumabEpidermal Growth FactorMonoclonal AntibodiesCD19View all TopicsDownload as PDFSet alertAbout this pageHemophilia ASurbhi Saini MBBS, Amy L. Dunn MD, in Transfusion Medicine and Hemostasis (Third Edition), 2019Nonfactor Replacement ProductsDevelopment of a recombinant, monoclonal bispecific antibody that mimics the actions of the intrinsic tenase complex (Hemlibra ®, Emicizumab-kxwh), and hence obviates the need for FVIII replacement, has been a significant milestone in the treatment of patients with hemophilia A and inhibitors. A recently concluded phase III trial of this molecule has demonstrated safety and efficacy with once-weekly subcutaneous dosing.The concept of \"rebalancing hemostasis” and thus increasing thrombin generation has been applied to the development of another category of products to treat hemophilia. Fitusiran (ALN-AT3SC), a small interfering RNA that decreases natural antithrombin levels, is currently undergoing an open label extension trial. Concizumab (monoclonal anti-TFPI antibody), inhibits TFPI leading to increase in thrombin generation via the TF-FVIIa pathway. Preliminary clinical trials are being conducted.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128137260001100Biological Therapy of Non-Hodgkin s LymphomasAndrew Zelenetz M.D., Ph.D., in The Lymphomas (Second Edition), 2006ENGINEERED T CELLSIncubation of peripheral blood lymphocytes with cytokines can induce nonspecific cytotoxic antitumor effector cells such as LAK or CIK cells (see Nonspecific Immunotherapy section above). Another approach that has been used to expand autoreactive T cells is ex vivo expansion with beads doubly coated with anti-CD3 and anti-CD28 to provide a potent proliferative response.238 A Phase I study has been completed with cells using this approach in patients with relapsed/refractory NHL undergoing HDT/ASCT.239 Of 36 patients enrolled, 22 proceeded to HDT/ASCT and 17 received the ex vivo expanded T cells. Patients received escalating doses of T cells. Toxicity included fever and infusion reactions, as well as an episode of CHF at dose level 3. One Grade 3 CNS neurotoxicity occurred at dose level 2. Five patients developed a delayed lymphocytosis, and 10 patients had a relative lymphocytosis. In vivo, there was restoration of INF-γ secretion following intracellular stimulation with PMA (phorbol myristate acetate) and ionomycin but incomplete restoration of PHA (phytohemagglutinin) responsiveness. In this small study, it was impossible to determine if the infusion of these cells altered the clinical outcome. The technology of the ex vivo expansion has been optimized, and by varying the culture conditions (specifically the ratio of anti-CD28 to anti-CD3), antigen-specific T cells can be expanded.240 These cells are currently being evaluated in clinical trials in patients with CLL.Another approach to using T cells therapeutically is to engineer cytotoxic cells to recognize a specific antigen. Brentjens and colleagues at MSKCC have reported on the transduction of T cells with a chimeric antigen receptor capable of binding to CD19 on B cells, and the subsequent in vitro expansion of T cells with IL-15 and CD80 stimulation.241 These transduced T cells can kill tumors in a murine model system. Furthermore, the transduced T cells from a patient with CLL can lyse autologous CLL cells in vitro. This approach will be evaluated in clinical trials in CLL and NHL.Investigators from the City of Hope Medical Center (COH) and the FHCRC have used a similar approach, transducing T cells with a chimeric antigen receptor recognizing CD20.242,243 Following cloning and ex vivo expansion, the engineered T cells expressed INF-γ in response to binding to CD20. These cells can be expanded in the presence of lymphoma and IL-2. The cells can lyse fresh tumors from patients with FL, SLL, splenic marginal zone lymphoma (SMZL), CLL, and DLBCL. Phase I clinical trials have been initiated using these engineered T cells.Bispecific AntibodiesConventional monoclonal antibodies target tumors by the specificity of the variable region, and activate effector mechanism via the Fc domains (Fig. 15-3). Bispecific antibodies combine two targeting domains, one for the tumor, and a second for some form of effector. Bispecific antibodies have been derived by chemical coupling the Fab fragments from two antibodies or by somatic cell methods, and therefore have been a challenge to manufacture on a clinical scale. Newer molecular techniques have become available to engineer bispecific single-chain antibodies that may have some manufacturing advantages.244 There have been limited clinical trials with bispecific antibodies in lymphoid malignancies; however, some preliminary data are available.Hartmann and colleagues in Germany have studied a bispecific antibody, HRS-3/A9, in HD that recognizes CD30 on the tumor cell and CD16 (FcγRIIIA) on effector cells.245–247 In the initial Phase I trial, patients received up to 64 mg/m2, which was the maximum dose because of limited availability of HRS-3/A9. The treatment was well tolerated, although the development of HAMA antibodies was seen in 9 of 15 patients, and 4 patients developed allergic reactions precluding continued therapy. Nonetheless, two responses were seen among the 15 patients treated. In a subsequent trial, patients were treated with either a CI for 4 days or an every-other-day bolus schedule. In responding patients, re-treatment was attempted after 4 weeks, and in patients with stable disease, a second course was given after IL-2 treatment and followed by GM-CSF. Sixteen patients were treated with 1 CR and 3 PR; three responses occurred in patients receiving the bispecific antibody by CI. Two of the responses occurred after the first cycle of therapy. Five patients with stable disease (SD) after one cycle received cytokines plus HRS-3/A9, and two additional patients responded. The IL-2 significantly increased NK cell levels in all five patients treated. A larger study would be needed to confirm that CI and cytokines are important in the activity of HRS-3/A9. The major hurdle to further study has been the manufacture of the bsMAb.Another trial of a bsMAb in HD was conducted by Borchmann and colleagues using the bispecific antibody H22xKi-4.248 The bsMAb was derived from chemical coupling of Fab fragments of the anti-CD30 antibody Ki-4 and the humanized anti-CD64 (FcγRI) antibody. The resulting bsMAb binds to tumor cells and monocytes, neutrophils, and macrophages. Toxicity in this Phase I study included mild hypotension, tachycardia, fatigue, and fever. Ten patients were treated with escalating doses (1 to 20 mg/m2) every other day for four doses; four responses were seen, three PR and one CR. Further investigation is ongoing with this bsMAb.Manzke and colleagues conducted a Phase I study of a CD3xCD19 bsMAb for indolent lymphoma.249 The rationale was to recruit T cells and activate them in situ with an anti-CD28 antibody. In this pilot study, both the bsMAb and the anti-CD28 antibody were injected into a single site at increasing doses (30μg to 1600μg). Toxicity included injection-site erythema, particularly at the higher dose levels. HAMA developed in 5 of the 10 patients, and 2 patients had a locoregional response. Elevation of serum TNFα at 2 or 3 days post-therapy suggested activation of CD4-positive T cells. This study provided proof of concept that targeting T cells is possible.Other combinations of targets have been explored preclinically, including CD64xCD19 and CD64xCD37.250 Despite the provocative preclinical and clinical data, bsMAb has important practical limitations as a consequence of immunogenicity and manufacture. However, practical development will certainly depend on successful development of molecular bsMAbs that can address these important limitations.Immunotoxins and Ligand ToxinsArming antibodies with toxins is another approach to increasing antibody potency. Several immunotoxins have been investigated. Anti-B4 (anti-CD19)-blocked ricin was originally evaluated for treatment of B-cell NHL. Although early-phase clinical trials suggested some activity, a randomized Phase III trial for minimal residual disease following HDT/ASCT was negative, and further clinical development has been halted.54,251 Other evaluated immunotoxins—H65-RTA (ricin A) against CD5, RFB4-deglycosylated ricin A directed against CD25, and anti-Tac(Fv)-PE38 (pseudomonas endotoxin) against CD25—have all shown some clinical activity, but are associated with vascular leak syndrome, and limited by anti-immunotoxin antibodies.55,56,252One of the most clinically active immunotoxins to date has been BL22, a recombinant immunotoxin containing an anti-CD22 variable domain fused to truncated pseudomonas endotoxin.253 Thirty-one patients with B-cell lymphoma were enrolled in a dose escalation trial, 16 of whom had chemoresistant hairy cell leukemia (HCL). To diminish the inflammatory adverse effects, patients treated with ≥40 μg/kg of BL22 were given infliximab (anti-TNFα) and rofecoxib. Patients were treated at 3-week intervals if they did not have neutralizing antibodies. Among the 16 patients with HCL, 11 had a CR and 2 had a PR. Three patients relapsed from CR at 7, 8, and 12 months, and were reinduced into CR with BL22. Two patients developed reversible hemolytic uremic syndrome. Other toxicities included transient hypoalbuminemia and transaminases elevations. HA22, an engineered derivative of BL22 with increased cytotoxicity, has increased antitumor activity without increased toxicity in xenograft models and is a candidate for clinical development.254An alternative to targeting toxins to tumor cells is to integrate the toxin into a receptor ligand that binds with relative selectively to tumor cells. One such molecule is denileukin difitox, which is approved for the treatment of CTCL. The drug is a recombinant fusion toxin in which the native receptor-binding domain of diphtheria toxin has been replaced by human IL-2.255 In the Phase I study, the dose-limiting toxicity was reversible transaminase elevations; other toxicities included rash, nausea, chest tightness, fever, and creatinine elevation. Half of the patients developed an antibody response to the drug. Three of 18 patients had a clinical response that led to further clinical development. Olsen and colleagues reported the results of a Phase III trial of denileukin difitox in patients with CTCL who had been previously treated.256 The randomization was between 9 and 18 μg/kg/day for 5 days, every 3 weeks for up to eight cycles. Seventy-one patients were treated, with an ORR of 30% (PR 20%, CR 10%). The median response duration was 6.9 months, and there was no difference between the doses. The predominant adverse events included flu-like symptoms, infusion reactions, and vascular leak. Transient elevation of transaminase and hypoalbunemia was common. This established the clinical activity of denileukin difitox in CLCL, for which it is currently approved for clinical use. Other tumors express CD25, and the activity of the drug is being investigated in NHL and CLL.257Immunotoxins have shown activity, although toxicity is significant, and neutralizing antibodies are common. Further improvement in the technology is needed to improve efficacy and reduce toxicity.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780721600819500194Overview of Biopharmaceuticals and Comparison with Small-molecule Drug DevelopmentTheresa Reynolds, ... Thomas R. Gelzleichter, in Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics, 2013Bispecific antibodiesIn general, human (bivalent) IgGs are monospecific because both Fab arms have identical heavy and light chain structure. The one notable exception is IgG4, which contains considerable heterogeneity in Fab composition due to dynamic Fab arm exchange. IgG4 therapeutics, such as natalizumab, which targets the α4 arm of α4β1 and α4β7 integrins, have been shown to undergo dynamic Fab arm exchange with endogenous polyclonal IgG4 in clinical trial patients [84]. More recent clinical IgG4 candidates have incorporated a serine to proline substitution (S228P) to stabilize the hinge region, which is more analogous to the sequence found in IgG1 [85,86]. In contrast to conventional monospecific mAbs, therapeutic bispecific mAbs are designed to target two distinct epitopes, which can allow for binding to multiple targets or enable specific cell–cell interactions that would not be possible with monospecific mAbs. Currently, there are many platforms under development that utilize cross-linked antibody fragments or fully functional bispecific mAbs that are engineered with intact effector functions. Fc-mediated dimerization has also been used to produce bispecific tetravalent antibodies that contain two binding sites for each of two targets [87]. One novel technology generates what is referred to as a dual action antibody, where each of two identical Fabs maintains the ability to bind two distinct epitopes. Following normal affinity maturation for a specific target, a repertoire of antibody variants with mutations in the light chain complementarity determining region (CDR) are screened against a secondary target to optimize and maintain affinity to both distinct targets [88].Even more unique engineering of bispecific mAbs is exemplified by a strategy in which both tumor cell surface antigens and T cells involved in the antitumor response are linked by a bispecific T-cell engager (BiTE). BiTE antibodies are constructed from two short, flexibly linked, single-chain antibodies, which engage both CD3-bearing T lymphocytes and numerous targets expressed on tumor cells, such as CD19, EpCAM, and CEA [89]. Blinatumomab binds both CD19 antigen and the T-cell receptor (CD3) and when engaged to both targets, transiently activates T cells, thereby directly targeting cytolytic potential against CD19-bearing cells. One remarkable aspect of this approach is that blinatumomab has demonstrated partial and complete tumor remission at doses as low as 0.015 mg, which is many orders of magnitude lower than the dose required for conventional mAb tumor-targeting therapies [90]. However, that efficacy comes at a price as cytokine release-associated toxicities must be carefully managed. Catumaxomab, which is currently licensed in the EU for malignant ascites, contains Fabs that bind both CD3 antigen and EpCAM; however unlike the BiTE technology, this MAb also retains an Fc region with intact effector functions and thus is often referred to as a trifunctional antibody. This approach allows for tumor destruction by T cell–mediated lysis, ADCC, cell-mediated cytotoxicity and phagocytosis [91]. Similar approaches include ertumaxomab, which selectively cross-links CD3-expressing T cells and HER-2-neu-expressing tumor cells.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123948106000010Possibility to Partly Win the War Against CancerXin-Yuan Liu, ... Ming Zuo, in Recent Advances in Cancer Research and Therapy, 201221.3.4 Modification and Future Prospective of CIKHow to enhance CIK cells’ cytotoxicity against tumor cells is a key issue to date. There are many ways to approach it:1.First, interact with dendritic cells which are the main antigen presenting cells. Wang et al.122 compared autologous CIK cells, autologous DC-CIK cells, and semi-allogeneic DC-CIK cells and found that the semi-allogeneic DC-CIK cells significantly increased the proliferation capacity of CIK cells, improved the ratios of CD3+ CD56+ cells and CD3+CD8+ cells, promoted the secretion of IFN-γ, and maintained the activity of CIK cells.2.Another way is to use bispecific monoclonal antibody which simultaneously binds to CIK cells and a target-like tumor cells to be destroyed. Chan et al.123 reported that a mouse underwent adoptive transfer of CIK cells redirected with bispecific monoclonal antibody (BSAbxCA125 and BSAbxHer2) and had significant reduction in tumor burden and improvement in survival versus those treated with CIK cells alone.3.The third way is to transfect CIK cells with cytokine genes or oncolytic viruses. CIK cells transfected with the IL-7 gene possessed a significantly higher cytotoxic activity against various tumor cell lines (e.g., renal cell carcinoma, malignant melanoma, and colon carcinoma) than non-transfected CIK cells in vitro.124 Schmidt-Wolf et al.120 applied CIK cells transfected with the IL-2 gene to 10 patients with metastatic colorectal carcinoma, lymphoma, or renal cell carcinoma. It showed that the only side effect was fever in three patients. One patient with follicular lymphoma achieved a complete response and three patients remained with stable disease condition.4.The fourth way is the modification of CIK cells with oncolytic virus such as double-deleted vaccinia virus (vvDD) which can destruct tumor cells and enable genes expressing anticancer proteins to be delivered specifically to the tumor site also displayed a 62% increase in complete responses against the CIK resistant SKOV-3 tumor-bearing mouse compared with just the vvDD vector (p=0.0379).1255.CIK will be further modified by sIFN-I which has super antitumor effects and also modified by the targeting gene-viro-therapy which may be better than the above vvDD protocol.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780123978332000212Are Vaccinations for Prostate Cancer Realistic?D. Robert Siemens, Timothy L. Ratliff, in Prostate Cancer, 2003Passive immunotherapyPassive immunization involves administrating antibodies to the patient that will bind specific tumor antigens to kill those cells selectively. Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein expressed by prostate epithelial cells and is overexpressed in prostate cancer, including advanced stages. PSMA-specific monoclonal antibodies have been developed and may have a novel therapeutic application.81,82 Kahn and associates have recently reported on a phase II clinical radioimmunotherapy trial utilizing capromab pendetide (PSMA monoclonal antibody) labeled with yttrium.83 Unfortunately, serum PSA was not lowered in the eight men with biochemical failure after prostatectomy and significant bone marrow toxicity was observed. Katzenwadel et al. have also described the construction of a bispecific monoclonal antibody to PSA and the T-cell associated CD3 antigen to increase the antigen-specific cytotoxicity of T cells.84 They demonstrated specific lysis of PSA expressing cells in vitro as well as reduction of tumor growth in vivo. Sinha and associates have also used an anti-PSA immunoglobulin G as a carrier for chemotherapeutic drugs (5-fluoro-2′-deoxyuridine) and have shown antitumor effects on LNCaP xenografts in nude mice.85Adoptive immunotherapy is another passive, but non-specific, strategy involving the transfer of immunologically activated lymphoid cells. Clinical experience with renal cell carcinoma has revealed that the activation of human lymphoid cells (i.e. IL-2 activated LAK cells) is feasible and that systemic administration is safe.86–88 Lubaroff et al. have shown that a severe combined immunodeficiency (SCID) mouse model is a viable system for studying adoptive therapies for human prostate cancer89 and that antitumor activity has been demonstrated utilizing autologous IL-2-activated tumor-infiltrating lymphocytes (TILs) (personal communication). A novel approach to adoptive therapy was reported by Cesano et al. whereby the human T-cell line (TALL-104), which is marked by an MHC non-restricted cytotoxic activity against a wide range of tumors across several species, demonstrated significant antitumor effect against DU-145 tumors in SCID mice.90 Gong and associates recently reported on the transduction of artificial receptors (specific for PSMA) into the T lymphocytes of patients with prostate cancer.91 They were able to demonstrate lysis of cancer cells in vitro and support the possibility of adoptive immunotherapy in prostate cancer patients.An alternative immunotherapeutic strategy to simply administering cytokines or activated Immune cell populations systemically is generating a vaccine that can elicit a specific antitumor response in vivo. There are generally two ways of categorizing cancer vaccines, depending on the source of the immunizing antigens: antigen-specific or tumor cell vaccines.67View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780122869815500604Anti-Amyloid-β Immunotherapy for Alzheimer’s DiseaseH. Crehan, C.A. Lemere, in Developing Therapeutics for Alzheimer s Disease, 2016Summary and conclusionsDespite the initial setback following the AN1972 trial, immunotherapy still remains a promising therapeutic approach for AD. The field has expanded over the past 15 years, and although there have been some promising results, a number of hurdles remain. Target engagement has been demonstrated in many of the clinical trials, although intervention may have come too late to save neurons lost long ago to the disease. ARIA has occurred with several passive anti-Aβ vaccines as a transient adverse effect that is dose- and ApoE4-dependent. Thus far, there has been a lack of robust cognitive or functional efficacy in moderate or severe AD patients. However, evidence for cognitive efficacy has been observed in prodromal and mild AD patients as demonstrated in the recent trials with solanuzumab and aducanumab.Penetration of the antibodies into the brain prevails as a major challenge with this type of treatment, as only a small percentage (0.1%) of antibodies have the ability to cross the blood–brain barrier (BBB) (Banks et al., 2002). Approaches to address this transport issue are being investigated, including different methods of delivery such as mAb-containing liposomes, which are coated with an antitransferrin receptor antibody, aiding in the passage across the BBB (Salvati et al., 2013). The transferrin receptor is normally present on endothelial cells and mediates the transfer of iron from the blood into the brain by endocytosis (Fishman et al., 1987). Interaction with this receptor may be leveraged to develop anti-Aβ drugs that have better access to the brain. The development of bispecific antibodies, otherwise known as brain shuttle constructs, whereby one Fab region targets Aβ and the other Fab region targets the transferrin receptor, has been investigated in a PS2-APP double transgenic mouse model of amyloidosis. In this model, the bispecific mAb demonstrated a greater penetration into the brain paranchyma and reduction in Aβ compared to monospecific anti-Aβ antibody (Niewoehner et al., 2014).It is now widely known that the pathophysiological process of AD starts years before clinical diagnosis of AD (Sperling et al., 2011a), which poses a huge obstacle to successful treatment. A number of anti-Aβ immunotherapy clinical trials have tested these agents in cohorts consisting of mild-to-moderate AD patients. The failure of these agents to provide fully efficacious results is most likely due to the late stage of administration and/or the ability of sufficient antibodies to enter the brain. The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study is novel in that the overall goal is to test antiamyloid treatments in the \"correct” population. This study, headed by Dr. Reisa Sperling (Brigham and Women’s Hospital) and sponsored by the National Institutes of Health (NIH), Eli Lilly, the Alzheimer’s Association, and others, will test Aβ immunotherapy using solanezumab in older people without dementia but with amyloid-positive PET scans, a cohort at high risk for AD (http://www.a4study.org). Other trials are following suit and seeking to recruit prodromal AD study cohorts. The high costs involved with continuous passive immunotherapy with externally generated antibodies make this therapy more applicable to secondary prevention in AD following the deposition of Aβ plaques rather than long-term primary prevention in people without plaques, unless they are at high genetic risk for AD. The ability to quickly cease treatment makes this an alluring method, especially with the documented ARIA and microhemorrhage cases reported during treatment in trials.Active vaccination may be a suitable early treatment method for preventing the downstream neurotoxicity and neuronal death observed in AD and subsequent cognitive deficits by clearance of Aβ prior to its aggregation and deposition. This long-lasting treatment would be similar to preventive vaccinations currently available for other conditions such as hepatitis B. Moreover, vaccination against Aβ would require fewer injections due to the activated immune response elicited, making it an attractive, cost-effective therapy. Active immunotherapy as a preventive AD therapy would need to be used with caution, as it may be difficult to terminate the immune response to the vaccine. However, the safety issues may be less of a concern in preplaque and pre-CAA individuals, and it is likely that younger people may generate more robust titers than their elder counterparts. In general, active Aβ immunotherapy may represent an effective and efficient way to prevent AD if given prior to or in the very early stages of the onset of Aβ pathogenesis.The need for an effective treatment is obvious, considering the increasingly growing medical and economic burden of AD. Investigating anti-Aβ immunotherapy in a prodromal AD population together with improving the vaccines’ targets may lead to more successful outcomes in the clinic. We remain optimistic that earlier treatment with anti-Aβ vaccines may protect against AD.View chapterPurchase bookRead full chapterURL: https://www.sciencedirect.com/science/article/pii/B9780128021736000071Targeting the neural cell adhesion molecule in cancerMarkus Jensen, Frank Berthold, in Cancer Letters, 20076 Bi-specific antibodiesBi-specific monoclonal antibodies (bi-mAbs) are bivalent molecules that can specifically bind to two different antigens: one antibody arm binds to a tumour associated antigen (TAA) on the surface of a malignant cell and the other arm binds to an activating surface molecule on a cytotoxic leukocyte to activate its killing potential [66,67]: consequently, leukocyte activity is redirected towards the malignant cell. Recent experimental data underline the importance of additional immune activation via the antibody’s Fc-part by interacting with Fcγ-receptors on monocytes, macrophages or dendritic cells [68].Bi-specific Abs of the CD3/TAA type can recruit T cells via CD3/TcR complex (CD3/T cell receptor complex) activation. This bi-mAb type repeatedly demonstrated strong clinical activity against malignant ascitic fluid after intraperitoneal application [69–74]. A CD3/EpCAM bi-specific Ab is currently being studied in a phase III trial in patients with intraperitoneal spreading EpCAM positive cancer with ascitic fluid and demonstrates significant clinical therapeutical activity [75]. This rat/murine bi-specific antibody named Catumaxomab has a chance to become the first bi-specific antibody approved [75] for clinical use.A single trial has investigated bi-specific CD3/TAA locoregional anti-NCAM treatment. Nitta et al. reported on 10 patients suffering from advanced NCAM positive glioblastoma forming necrotic tumour cavities. Patients received intracavitary application of autologous LAK cells (ex vivo IL-2 activated autologous PBMC) armed with CD3/NCAM bi-specific antibodies. Bi-specific Abs were generated by chemically x-linking the native monoclonal murine Abs OKT3 (anti-CD3) and NE150 (anti-NCAM). Clinical response was achieved in 8 out of 10 Patients (4 × CR, 4 × PR) after treatment with bi-specific antibodies plus LAK cells. In contrast, intracavitary treatment of 10 other patients with LAK cells alone did not result in any clinical response. These investigations indicated that this bi-specific approach can be feasible and efficient [76].Unfortunately locoregional treatment can only be applied to a minority of cancer patients with tumour growth in a native cavity such as the peritoneum or tumour growth forming necrotic cysts. While locoregional treatment with murine CD3/TAA bi-mAbs appears to be a feasible treatment method, systemic treatment (e.g. intravenous application), which would be required for all other patients, faces a number of unsolved technical problems. Cost effective generation and mass production of humanized (large amounts are required for intravenous application) bi-specific antibodies has not been achieved up to now. The alternative, recombinant bi-specific antibodies which have a reduced immunogenicity, such as bi-specific single chain antibodies or diabodies have the disadvantage that their half lives are too short due to fast renal elimination and protein instability in human serum [77]. Fast progress in antibody engineering technology might help to overcome these limitations in near future but at the moment these limitations effectively impede clinical study activity.A CD3/NCAM bi-specific antibody differs greatly from other CD3/TAA bi-specific Abs in a very specific immunobiologic aspect: CD3/NCAM bi-mAb always link CD3-positive T cells with NCAM expressing natural killer cells first before T cells can be redirected to cancer cells. Both T cells and NK cells represent strong cytotoxic and immunomodulatory effector cell classes, which are pushed into interaction by the bi-specific Ab with an uncertain final impact on the functional status of the T cell. It is unclear whether T cells are able to attack cancer cells after this preconditioning or whether they become anergic. These complex interactions were recently studied using the murine CD3/NCAM bi-specific antibody (OKT3/ERIC1).The function of a murine CD3/NCAM bi-specific antibody (OKT3/ERIC1) was investigated. First it could be shown that the CD3/NCAM bi-mAbs indeed are able to activate T cells in the presence of NK cells to proliferate and mount cytotoxic action against NCAM positive neuroblastoma cells. Importantly, NK cells were almost completely depleted during the T cell activation phase by the bi-specific Ab. Surprisingly, the number of NK cells present during T cell activation phase positively correlated with the strength of T cell cytotoxicity against NCAM+ cancer cells [78]. This supports the hypothesis of an \"enhancement function” exercised by NK cells on T cells.Further phenotype analyses demonstrated that activated T cells can differentiate into a larger CCR7+/CD45RA- and a smaller CCR7−/CD45RA-population. According to Sallusto et al. CCR7−/CD45RA-T cells represent so called \"effector memory cells” (TEM cells) which possess immediate effector functions and express receptors which enable active T cell migration into malignant tissues [79,80]. This would be a desired property of T cells after bi-specific activation. Subsequent analysis revealed that very low doses of the CD3/NCAM bi-specific antibody can enhance tetanus toxoid (Th1 model antigen) specific T cell responses demonstrating that a CD3/NCAM bi-mAb can synergize with TCR-restricted T cell responses [81]. This observation might be meaningful for the induction of long lasting T cell responses.However these pioneering results highlight the CD3/NCAM bi-specific antibodies as unique immunomodulators which initiate complex cellular reactions that can be employed for the fight against cancer. However, all experiments on CD3/NCAM bi-mAbs are still done on the in vitro level and still require confirmation by an in vivo experimental system.View articleRead full articleURL: https://www.sciencedirect.com/science/article/pii/S0304383507004247Immune-Based Therapies in Acute LeukemiaMatthew T. Witkowski, ... Iannis Aifantis, in Trends in Cancer, 2019BiTEs are bi-specific monoclonal antibodies that simultaneously target T cells and tumor cells, thus forming a direct physical link between them [138]. This leads to killing of the tumor cell by the T cell, independently of MHC-I or interaction with costimulatory receptors [138]. BiTEs are an attractive treatment because they represent an off the shelf strategy, unlike CAR-T cells that must be uniquely tailored for each patient. Another attractive possibility is targeting of NK cells in the tumor microenvironment using bi-specific killer cell engagers (BiKEs) or tri-specific killer cell engagers (TriKEs). These are bi-specific antibodies targeting a tumor cell antigen and CD16 that is expressed on NK cells (BiKE) [139], or antibodies targeting a tumor antigen and CD16 combined with IL-15, inducing NK cell expansion (TriKE) [140]. Linkage of tumor and NK cells induces tumor cell killing by the NK cells.View articleRead full articleURL: https://www.sciencedirect.com/science/article/pii/S2405803319301487New therapeutic approaches in breast cancerEleri Davies, Stephen Hiscox, in Maturitas, 20113.2.3.2 ErtumaxomabErtumaxomab is a bi-specific monoclonal antibody targeting HER2 and the CD3 receptor. This enables the antibody to simultaneously bind both HER2+ tumour cells and CD3-expressing T-cells. In addition, ertumaxomab simultaneously binds Fcγ receptor expressing accessory cells via its Fc domain [56]. Interactions with these cell types results in activation of T-cells, which can destroy the HER2+ tumour cells through release of lytic enzymes, and stimulation of phagocytosis via the activity of Fcγ receptor-positive cells such as macrophages. In phase I clinical trials, ertumaxomab treatment resulted in antitumour responses in patients with MBC. Recent reports have demonstrated that ertumaxomab is also able to induce cytotoxicity in various tumour cell lines, including those with low HER2 antigen density [57] and thus may provide a novel therapeutic option for breast cancer patients not eligible for trastuzumab. A recent phase I study in 17 HER2+ metastatic breast cancer patients demonstrated that ertumaxomab treatment induced a strong immunogenic response and resulted in tumour response in a third of patients [56]. To this end, ertumaxomab is currently under investigation in phase II studies in MBC patients irrespective of HER2 gene amplification [58].View articleRead full articleURL: https://www.sciencedirect.com/science/article/pii/S0378512210003907Armed oncolytic viruses: A kick-start for anti-tumor immunityJ.F. de Graaf, ... B.G. van den Hoogen, in Cytokine Growth Factor Reviews, 20183.4.3 BiTEsBiTEs (bispecific T cell engagers) are a class of bispecific monoclonal antibodies that have shown promising anti-tumor effects [104]. However, they have a very short half-life and therefore require continuous infusion. Vaccinia virus (VV) armed with a BiTE with specificity for the TCR and a TAA was tested in a xenograft lung cancer mouse model. The study showed increased tumor cell killing through T cell activation and skewing towards Th1 responses [105]. A disadvantage of BiTEs is that they target only one TAA and therefore stimulate the immune response directed to only that TAA, while other immune-modulatory transgenes induce immunity to multiple TAAs that are released by dying tumor cells.Read full articleView PDFRead full articleURL: https://www.sciencedirect.com/science/article/pii/S1359610118300352Recommended publicationsInfo iconJournal of Chromatography BJournalBiochemical and Biophysical Research CommunicationsJournalStructureJournalCancer LettersJournalBrowse books and journalsAbout ScienceDirectRemote accessShopping cartAdvertiseContact and supportTerms and conditionsPrivacy policyWe use cookies to help provide and enhance our service and tailor content and ads. By continuing you agree to the use of cookies.Copyright © 2021 Elsevier B.V. or its licensors or contributors. ScienceDirect ® is a registered trademark of Elsevier B.V.ScienceDirect ® is a registered trademark of Elsevier B.V.