Bispecific Antibodies

A significant disadvantage of such small structures is their low half-life in the blood, which requires frequent injection of the drug. Two antigen-binding sites against each of the antigens and the lack of Fc increase the molecular weight and in vivo stability of these BsAbs. Blinatumomab and catumaxomab, approved for use as medicines, are designed to treat oncological diseases. In perspective, one can expect the construction of new platforms that will allow development of full processes from BsAb expression to preclinical tests.

To develop new antitumor drugs, it is necessary to search for new combinations of BsAb targets to increase the therapeutic effect and reduce side effects; specific features of tumors also should be taken into account. BsAbs can be used in combination with other medications, eg, drugs controlling the cell cycle, indoleamine dioxygenase inhibitors, and vaccines.

There is no doubt that continuous development of new approaches to BsAb production is required to control oncological diseases. The design of new BsAbs will likely include the ability to bind two or more tumor antigens in combination with the attraction of T lymphocytes and assistant cells into the immunosynapse. Of particular importance is the increase in BsAb specificity and sensitivity, as well as reducing cytotoxicity to nontumor cells.

Other important tasks are increasing BsAb yield from hybridomas and decreasing the cost of the drugs. A promising work on short nonviral minicircle DNA for the synthesis of BsAbs in vivo was recently published. In a short time, one may expect the completion of clinical trials and approval of BsAbs directed to treat autoimmune and other diseases.

It has been shown that BsAbs directed against the CD4- and V3-binding sites on the Env gp protein exhibit a synergistic effect in vivo and in vitro. The design of bispecific molecules demands analysis of the required BsAb properties affinity to target molecules, pharmacokinetics in blood, and near target cells and mechanisms of action.

Bispecific antibodies: design, therapy, perspectives

The increasing number of therapeutic BsAbs entering clinical trials and results of BsAb use in clinical medicine may improve understanding of their pharmacokinetics in the near future. The ideal therapeutic BsAbs are expected to have a long half-life in human blood, distribution among organs, and sufficient penetration of tissue. The use of BsAbs in diagnostic tools is very promising, since BsAbs simplify the detection of target antigens.

BsAbs are used in sensitive immunoassays developed for simple and rapid detection of bacterial and viral infectious diseases and in cancer diagnostics. The use of BsAbs and I-labeled haptens allows pretargeting human prostate cancer xenografts in severe combined immunodeficient mice.

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With minimal signal background and high sensitivity and specificity, the use of BsAbs in this method is superior to mAbs. The BsAb specific to lipoarabinomannan and horseradish peroxidase was developed with quadroma technology. Results were obtained within 2 hours of sample collection, which is very competitive compared to the standard laboratory-culture method, where results are obtained 2—6 weeks after sampling.

The quadroma expressing BsAbs against Escherichia coli lipopolysaccharide and whole bacteria in combination with horseradish peroxidase was used for rapid one-step sandwich enzyme-linked immunosorbent-assay detection of the E. A quadroma producing anti- B.

The assay is highly sensitive and specific, due to release of a bound fluorescent reporter from a BsAb-active center after binding to the thermonuclease-specific antigen of S. The development of new methods of BsAb generation made it possible to obtain various variants of promising Ab derivatives for use in therapy.

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The resulting BsAbs differ from natural IgG by pharmacokinetics, blood serum half-life, ability to penetrate tumors, size, valence, and presence of Fc. Simultaneous blocking of several biological pathways allows BsAbs to exhibit a synergistic effect unachievable with a mixture of monospecific Abs. The results of recent years indicate that in the close future, by combinations of methods developed earlier, new BsAbs directed against a variety of diseases in which simultaneous binding of several specific antigens can play a key role will be generated.

The potential of simultaneous detection of several antigens or combining antigen-binding sites with assay markers makes BsAbs an important object of further research in biomedicine, pharmacology, and diagnostics. National Center for Biotechnology Information , U. Drug Des Devel Ther. Published online Jan Author information Copyright and License information Disclaimer.

Bispecific antibodies for cancer therapy

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https: By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. This article has been cited by other articles in PMC. Abstract Antibodies Abs containing two different antigen-binding sites in one molecule are called bispecific.

Introduction Immunoglobulins antibodies [Abs] are major protein components of the adaptive immune system, directed against foreign compounds and infectious agents. Open in a separate window. Catumaxomab Catumaxomab Removab, Trion was the first bispecific trifunctional drug approved in by the European Medicines Agency for the treatment of malignant ascites. Other BsAbs undergoing preclinical and clinical trials Most of the antitumor BsAbs currently undergoing clinical and preclinical trials, such as blinatumomab and catumaxomab, contain one anti-CD3 antigen-binding site, attracting the T lymphocyte to the tumor cell.

Architecture of common BsAbs formats. Table 1 Clinical trials of bispecific antibodies. Table 2 Terminated clinical trials of therapeutic bispecific antibodies. Adverse effects of BsAb treatment Like other methods of therapy for severe diseases, therapeutic BsAbs cause different side effects, the most common of which are nausea, vomiting, abdominal pain, fatigue, leukopenia, neutropenia, and thrombopenia.

History and methods of bispecific antibody generation The first work on BsAb generation was published in and described the production of chimeric BsAbs containing simultaneously two different antigen-binding sites from a mixture of two monospecific Abs. Chemical conjugation and covalent attachment of fragments BsAbs can be generated by the attachment of light or heavy chains, single-domain Abs, single-chain variable fragment scFv , or other genetic engineering structures with additional antigen-binding sites to the amino or carboxyl ends of monospecific IgG molecules.

Protein, cellular, and genetic engineering Coexpression of two heavy- and two light-chain genes in one cell may result in expression of IgG-like molecules. Perspectives Blinatumomab and catumaxomab, approved for use as medicines, are designed to treat oncological diseases. Conclusion The development of new methods of BsAb generation made it possible to obtain various variants of promising Ab derivatives for use in therapy.

Footnotes Disclosure The authors report no conflicts of interest in this work. Mechanisms of action of therapeutic antibodies for cancer. Alternative molecular formats and therapeutic applications for bispecific antibodies. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair. N Engl J Med. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Brinkmann U, Kontermann RE.

The making of bispecific antibodies. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Novel therapies for immune-mediated inflammatory diseases: A revolutionary therapeutic approach for psoriasis: Expert Opin Investig Drugs. The development of bispecific antibodies and their applications in tumor immune escape. Dual targeting strategies with bispecific antibodies. Bispecific antibody therapeutics market. Thakur A, Lum LG. Expert Opin Biol Ther. Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody.

Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia.

Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: The coming of age of engineered multivalent antibodies. Goebeler ME, Bargou R. Bispecific antibodies in cancer therapy. CDtargeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Targeting T cells to tumor cells using bispecific antibodies.

Curr Opin Chem Biol. Antibody therapy of cancer. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Immunotherapy of peritoneal carcinomatosis with the antibody catumaxomab in colon, gastric, or pancreatic cancer: A phase I trial of intravenous catumaxomab: Baeuerle PA, Reinhardt C.

Bispecific T-cell engaging antibodies for cancer therapy. Potent immunomodulatory effects of the trifunctional antibody catumaxomab. Ruf P, Lindhofer H. Kontermann RE, Brinkmann U. Humoral response to catumaxomab correlates with clinical outcome: Clinical pharmacology and translational aspects of bispecific antibodies. Translation and clinical development of bispecific T cell engaging antibodies for cancer treatment. Bispecific antibodies as a development platform for new concepts and treatment strategies. Int J Mol Sci. Watch a time-lapse microscope video of the T-cell bispecific antibody in activating cytotoxic T lymphocytes designed to kill tumor cells.

As demonstrated in preclinical models, upon dispersion of T-cell bispecific antibodies, the cytotoxic T cells seen in red immediately recognize and begin to destroy the target cancer cells seen in blue. Green flashes in the tumor cells indicate imminent T-cell—induced cell death. This compound and its use continues to be investigated in ongoing studies; efficacy and safety have not been established. The link you have selected will take you away from this site to one that is not owned or controlled by Genentech, Inc. Genentech does not recommend and does not endorse the content on any third-party websites.

Your use of third-party websites is at your own risk and subject to the terms and conditions of use for such sites. The information contained in this section of the site is intended for U. Click "OK" if you are a healthcare professional. Explore by Tumor Type. Safety Explore by Tumor Type. Explore T-cell Bispecific Antibodies.

Studies performed in xenografted nude mice that compared TF4 as a pretargeting agent of an In-HSG-peptide with a one step approach using the parental anti-CD20 mAb hA20 directly labeled with 90 Y demonstrated an impressive 1,fold improvement of the tumor-to-blood ratio, as well as a 1. The high therapeutic potential of this approach should thus soon be tested in the clinic.

After years of disappointment and frustrations, clinical trials of bsAbs Table 1 are finally providing exciting results, with the most impressive ones being delivered by triomab and BiTE molecules. These results do not represent a mere improvement compared to those obtained by approved therapeutic antibodies, but are a real leap in terms of therapeutic efficiency. For the first time, the possibility of actually curing patients using antibodies seems within reach. Further randomized studies are eagerly awaited to demonstrate whether these encouraging results from Phase 1 and 2 trials will result in prolonged overall survival.

Interestingly, after a race toward fully human antibody molecules experienced during the last decade, these impressive biological activities were obtained with fully murine molecules which, because of their high efficiency, can be injected in doses four to five log lower than those usually used by therapeutic mAbs.

In the case of BiTEs, the short half life traditionally perceived as a limitation was actually exploited to achieve an exquisite control of drug levels in patients using mini-pump devices developed for insulin delivery. By choosing to develop treatments for malignant ascites and ALL, Trion Pharma, which produces triomabs, and Micromet, which produces BiTE molecules, have decided to pursue approval for niche indications. This approach is likely to be the fastest and safest route to approval. There is no doubt that both companies have promising candidates with very large potential markets, and that candidates against several malignancies will soon be tested in clinical trials.

With these developments, it might well be that we are currently experiencing a turning point in the field of bispecific antibody and more generally of cancer immunotherapy. National Center for Biotechnology Information , U.

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Journal List MAbs v. Patrick Chames and Daniel Baty. Author information Article notes Copyright and License information Disclaimer. Received Aug 14; Accepted Sep 8. This article has been cited by other articles in PMC. Abstract With 23 approvals in the US and other countries and four approvals outside US, antibodies are now widely recognized as therapeutic molecules. Introduction Monoclonal antibodies mAbs are endowed with exquisite specificities.

Chemically Cross-Linked Bispecific Antibodies The potential of using bispecific antibodies to retarget effector cells toward tumor cells was demonstrated in the s 3 , 6 , 7 and, several Phase 1 clinical studies were launched in the early nineties. TriomAbs Triomabs probably represent one of the most impressive and unexpected success in the field of bispecific antibodies. Recombinant bsAbs In the nineties, advances in antibody engineering provided innovative solutions antibody design problems, allowing production of small antibody fragments recapitulating the entire binding activity of the parent molecule Fig.

Open in a separate window. Bispecific T Cell Engagers Another type of tandem scFvs aimed at activating T cells has met with more success in clinical trials. Conclusion After years of disappointment and frustrations, clinical trials of bsAbs Table 1 are finally providing exciting results, with the most impressive ones being delivered by triomab and BiTE molecules. Table 1 Most recent clinical trials involving the use of bispecific antibodies.

Footnotes Previously published online: Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Hybrid antibodies can target sites for attack by T cells. Chames P, Baty D. Bispecific antibodies for cancer therapy. Curr Opin Drug Discov Devel.

Single-domain antibodies as building blocks for novel therapeutics.

Production of Target-Specific Effector cells using hetero-crosslinked aggregates containing anti-target cell and anti-Fc-gamma receptor antibodies. Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody. A revival of bispecific antibodies. Clinical experience with CDdirected immunotherapy. A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors. The new face of bispecific antibodies: Implications for a single-step purification of bispecific antibodies.

The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing.

The emerging role of EpCAM in cancer and stem cell signaling. Ruf P, Lindhofer H. Induction of a long-lasting antitumor immunity by a trifunctional bispecific antibody. Immunotherapy of malignant ascites with trifunctional antibodies. The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor 2. Two new trifunctional antibodies for the therapy of human malignant melanoma. Orientation of antigen binding sites in dimeric and trimeric single chain Fv antibody fragments. Muller D, Kontermann RE.

Recombinant bispecific antibodies for cellular cancer immunotherapy. Curr Opin Mol Ther. A bispecific diabody directed against prostate-specific membrane antigen and CD3 induces T-cell mediated lysis of prostate cancer cells. A recombinant bispecific single-chain antibody induces targeted, supra-agonistic CDstimulation and tumor cell killing.

A bispecific single-chain antibody that mediates target cell-restricted, supra-agonistic CD28 stimulation and killing of lymphoma cells. N Engl J Med. Supraagonistic, bispecific single-chain antibody purified from the serum of cloned, transgenic cows induces T-cell-mediated killing of glioblastoma cells in vitro and in vivo. A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity.