Antibody therapeutics are now established as a major drug class. Here, Carter and Lazar comprehensively discuss current and emerging platforms and technologies for antibody therapeutics, with an emphasis on approaches that could extend their therapeutic applications, including antibody–drug conjugates, bispecific antibodies and antibody engineering to enable more effective delivery.

Next generation antibody drugs: pursuit of the 'high-hanging fruit'.

Immuno-oncology approaches have entered clinical practice, with tremendous progress particularly in the field of T cell-engaging therapies over the past decade. Herein, we provide an overview of the current status of bispecific T cell engager (BiTE) therapy, considering the unprecedented new indication for such therapy in combating minimal (or measurable) residual disease in patients with acute lymphoblastic leukaemia, and the development of novel approaches based on this concept. Key aspects that we discuss include the current clinical data, challenges relating to treatment administration and patient monitoring, toxicities and resistance to treatment, and novel strategies to overcome these hurdles as well as to broaden the indications for BiTE therapy, particularly to common solid cancers. Elucidation of mechanisms of resistance and immune escape and new technologies used in drug development pave the way for new and more-effective therapies and rational combinatorial approaches. In particular, we highlight novel therapeutic agents, such as bifunctional checkpoint-inhibitory T cell engagers (CiTEs), simultaneous multiple interaction T cell engagers (SMITEs), trispecific killer engagers (TriKEs) and BiTE-expressing chimeric antigen receptor (CAR) T cells (CART.BiTE cells), designed to integrate various immune functions into one molecule or a single cellular vector and thereby enhance efficacy without compromising safety. We also discuss the targeting of intracellular tumour-associated epitopes using bispecific constructs with T cell receptor (TCR)-derived, rather than an antibody-based, antigen-recognition domains, termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs), which might broaden the armamentarium of T cell-engaging therapies. The use of bispecific antibodies to engage cells of the immune system that are cytotoxic to cancer cells is a major focus of cancer immunotherapy, with approvals for the treatment of acute lymphoblastic leukaemia. Here, the authors review the clinical results obtained with bispecific antibodies to date. They also discuss the challenges associated with this therapeutic approach and the proposed solutions aimed at preventing or minimizing toxicities, countering immune escape and broadening the indications for these treatments.

T cell-engaging therapies - BiTEs and beyond.

https://pure.rug.nl/ws/files/96958859/A_review_of_bispecific_antibodies_and_antibody_constructs_in_oncology_and_clinical_challenges.pdf

A review of bispecific antibodies and antibody constructs in oncology and clinical challenges

With the current biotherapeutic market dominated by antibody molecules, bispecific antibodies represent a key component of the next-generation of antibody therapy. Bispecific antibodies can target two different antigens at the same time, such as simultaneously binding tumor cell receptors and recruiting cytotoxic immune cells. Structural diversity has been fast-growing in the bispecific antibody field, creating a plethora of novel bispecific antibody scaffolds, which provide great functional variety. Two common formats of bispecific antibodies on the market are the single-chain variable fragment (scFv)-based (no Fc fragment) antibody and the full-length IgG-like asymmetric antibody. Unlike the conventional monoclonal antibodies, great production challenges with respect to the quantity, quality, and stability of bispecific antibodies have hampered their wider clinical application and acceptance. In this review, we focus on these two major bispecific types and describe recent advances in the design, production, and quality of these molecules, which will enable this important class of biologics to reach their therapeutic potential.

Design and Production of Bispecific Antibodies.

Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical therapeutic effects of BsAbs are superior to those of monoclonal antibodies (MoAbs), with broad applications for tumor immunotherapy as well as for the treatment of other diseases. Recently, with progress in antibody or protein engineering and recombinant DNA technology, various platforms for generating different types of BsAbs based on novel strategies, for various uses, have been established. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. The detailed mechanisms of clinical/therapeutic action have been demonstrated with these different types of BsAbs. Three kinds of BsAbs have received market approval, and more than 110 types of BsAbs are at various stages of clinical trials. In this paper, we elaborate on the classic platforms, mechanisms, and applications of BsAbs. We hope that this review can stimulate new ideas for the development of BsAbs and improve current clinical strategies.

/pdf/bispecific-antibodies-from-research-to-clinical-application-3otv8ywu85.pdf

Bispecific Antibodies: From Research to Clinical Application.

The present invention provides to a antibody construct comprising a first human binding domain capable of binding to human CDH19 on the surface of a target cell and a second domain capable of binding to human CD3 on the surface of a T cell. Moreover, the invention relates to a nucleic acid sequence encoding the antibody construct, a vector comprising said nucleic acid sequence and a host cell transformed or transfected with said vector. Furthermore, the invention relates a process for the production of the antibody construct of the invention, a medical use of said antibody construct and a kit comprising said antibody construct.

Antibody constructs for cdh19 and cd3

T cell engaging bispecific antibody constructs (BiTE®), such as blinatumomab which targets CD19-positive cells, have shown great promise for treating certain CD19-positive hematological malignancies. Blinatumomab comprises a single chain Fv (scFv) that binds CD19 and a scFv that targets the T cell CD3 protein. The molecular weight of this “canonical” BiTE® is ~ 55 kDa, making it susceptible to kidney-mediated clearance and resulting in a short serum half-life (~ 4 hours). To maintain effective serum concentrations, canonical BiTE® antibody constructs must be administered by continuous IV (cIV) infusion. While there are many advantages associated with cIV administration (e.g., safety and uniform PK profile), patient convenience could be enhanced if the BiTE® antibody construct were compatible with once-weekly administration. To achieve this, the serum half-life of the BiTE® antibody construct would need to be extended. A canonical BiTE® targeting CD33 (AMG 330) is currently being evaluated in a phase I clinical trial. Like blinatumomab, AMG 330 is dosed cIV. To extend the serum half-life of AMG 330 and enable once-weekly dosing, several approaches were evaluated including fusion of AMG 330 to human albumin and Fc-containing moieties. Each of these half-life extended (HLE) constructs was evaluated in vitro, in mouse xenograft models and in non-human primates. In vitro assays evaluated 1) binding to both human and cynomolgus CD33 and CD3 proteins, and 2) cytotoxicity using human and cynomolgus target and effector cells. In each of these assays the canonical and HLE BiTE® antibody constructs demonstrated similar activity: single-digit nM binding and single digit pM cytotoxicity. Canonical and HLE BiTE® antibody constructs were subsequently evaluated in an orthotopic mouse model in which MOLM13 cells were administered IV and activated human T cells were administered IP two days later. The Fc-based HLE BiTE® antibody constructs provided a similar survival advantage when administered Q4D or Q5D as the canonical BiTE® when administered QD. However, the albumin fusion–based HLE BiTE® was less efficacious when administered Q4D than the QD- administered canonical BiTE®. Lastly, the PK/PD relationship was evaluated for each of the constructs in non-human primates. The serum half-lives varied from 6 hours for the canonical BiTE® to 44-167 hours for the HLE BiTE® antibody constructs. Each of the HLE BiTE® antibody constructs showed on-target depletion of CD33-positive monocytes and neutrophils in the blood and depletion of CD33-positive cells in the bone marrow. These data demonstrate that half-life extended BiTE® antibody constructs can be generated that retain comparable in vitro and in vivo activity as a canonical BiTE® and achieve a serum half-life compatible with once weekly dosing. Citation Format: Tara L. Arvedson, Mercedesz Balazs, Pamela Bogner, Kurt Black, Kevin Graham, Anja Henn, Matthias Friedrich, Patrick Hoffmann, Roman Kischel, Peter Kufer, Ralf Lutterbuese, Markus Muenz, Tobias Raum, Benno Rattel, Karen Rex, Dan Rock, Oliver Thomas, Joachim Wahl, Andreas Wolf, Angela Coxon. Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 55. doi:10.1158/1538-7445.AM2017-55

Abstract 55: Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing

Bispecific T cell engager (BiTE®) antibody constructs redirect T cells to induce lysis of tumor cells. The anti-CD19/CD3 BiTE® Blincyto® can deplete target cells in both the blood and tissue compartment in B cell malignancies, suggesting that the BiTE® mechanism of action will also be effective against solid tumors. The tumor differentiation antigen mesothelin (MSLN) is an attractive target for the BiTE® approach. MSLN is highly expressed in >80% of ovarian and pancreatic tumors and mesothelioma. Expression of MSLN in normal tissues appears restricted to mesothelial cell surfaces such as the pleural, pericardial, and peritoneal layer. Here, we report the preclinical characterization of an anti-MSLN/CD3 BiTE® antibody construct with extended half-life. The BiTE® antibody construct binds MSLN and CD3 with low nM affinity and has low pM cytotoxic activity against MSLN-positive ovarian, pancreatic and lung cancer cell lines in vitro. Activity of the anti-MSLN/CD3 BiTE® antibody construct is observed at low effector to target cell ratios, and in cancer cells that express low levels of MSLN. This BiTE® antibody construct is also cytotoxic to cell lines that are resistant to chemotherapy. In mice, significant tumor growth inhibition of an established ovarian tumor xenograft model was achieved by IV dosing of the anti-MSLN/CD3 BiTE® antibody construct every 5 days. Pharmacokinetic evaluation of the anti-MSLN/CD3 BiTE® antibody construct in non-human primates demonstrated a half-life of 4-10 days. The potency and specificity of the anti-MSLN/CD3 BiTE® antibody construct, together with projected ability to dose once a week IV in humans, supports development of this BiTE® for treatment of MSLN-positive tumors. Citation Format: Alexander Sternjak, Fei Lee, Joachim Wahl, Dan Rock, Oliver Thomas, Sabine Stienen, Ralf Lutterbuese, Patrick Hoffmann, Tobias Raum, Peter Kufer, Benno Rattel, Angela Coxon, Matthias Friedrich, Julie Bailis. Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3630. doi:10.1158/1538-7445.AM2017-3630

Abstract 3630: Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin

BiTE® therapeutics are single chain antibody constructs harboring two binding moieties: one directed at a tumor associated antigen and one directed at the CD3e protein, which trigger T cell dependent cellular cytotoxicity (TDCC) against targeted cancer cells. Here, we evaluated the suitability of ENPP3 as a potential BiTE® target. The ENPP3 mRNA is highly differentially expressed in clear cell Renal Cell Carcinoma (ccRCC) and the ENPP3 protein is detected with high uniformity and intensity in ccRCC tumor samples by immunohistochemistry. We demonstrated the surface expression of this protein in Renal Cancer cell lines and confirmed that the ENPP3 protein was highly restricted to the luminal side of normal epithelial layers in which it was detected (proximal renal tubules, bronchial epithelium, salivary glands). We developed highly potent anti-ENPP3 BiTE® molecules and demonstrated the in vitro TDCC activity of these molecules. Two anti-ENPP3 BiTE® molecules further demonstrated tumor formation inhibition activity in a human T cell / human target cell admixture mouse xenograft model. Citation Format: Olivier Nolan-Stevaux, Flordeliza Fajardo, Lily Liu, Suzanne Coberly, Patricia McElroy, Aaron Nazarian, Franziska Bott, Elisabeth Nahrwold, Tobias Raum, Roman Kischel, Ralf Lutterbuese, Patrick Hoffmann, Peter Kufer. Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 585.

Abstract 585: Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy

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Antibody constructs for cdh19 and cd3

Abstract 55: Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing

Abstract 3630: Preclinical evaluation of a BiTE® antibody construct with extended half-life that targets the tumor differentiation marker mesothelin

Abstract 585: Assessing ENPP3 as a renal cancer target for bispecific T-cell engager (BiTE) therapy