The state of the art of bispecific antibodies for treating human malignancies
2021; Springer Nature; Volume: 13; Issue: 9 Linguagem: Inglês
10.15252/emmm.202114291
ISSN1757-4684
AutoresShuhang Wang, Kun Chen, Qi Lei, Peiwen Ma, Andy Q. Yuan, Yong Zhao, Youwei Jiang, Fang Hong, Shujun Xing, Yuan Fang, Ning Jiang, Huilei Miao, Minghui Zhang, Shujun Sun, Zicheng Yu, Wei Tao, Qi Zhu, Yingjie Nie, Ning Li,
Tópico(s)Toxin Mechanisms and Immunotoxins
ResumoReview24 August 2021Open Access The state of the art of bispecific antibodies for treating human malignancies Shuhang Wang Shuhang Wang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Kun Chen Kun Chen orcid.org/0000-0002-1855-5149 NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non-profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003), Guizhou Provincial People's Hospital, Guiyang, China Search for more papers by this author Qi Lei Qi Lei orcid.org/0000-0003-1953-9236 Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Peiwen Ma Peiwen Ma Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Andy Qingan Yuan Andy Qingan Yuan orcid.org/0000-0001-6200-2544 Excyte Biopharma Ltd, Beijing, China Excyte LLC, Rockville, MD, USA Search for more papers by this author Yong Zhao Yong Zhao Nanjing Umab-biopharma Co., Ltd, Nanjing, China Search for more papers by this author Youwei Jiang Youwei Jiang Hangzhou Genekine Biotech Co., Ltd, Hangzhou, China Search for more papers by this author Hong Fang Hong Fang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Shujun Xing Shujun Xing Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Yuan Fang Yuan Fang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Ning Jiang Ning Jiang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Huilei Miao Huilei Miao Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Minghui Zhang Minghui Zhang Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China Search for more papers by this author Shujun Sun Shujun Sun Queen Mary School, Nanchang University, Nanchang, China Search for more papers by this author Zicheng Yu Zicheng Yu Geneplus, Shenzhen, China Search for more papers by this author Wei Tao Wei Tao China Pharmaceutical University, Nanjing, China Search for more papers by this author Qi Zhu Qi Zhu China Pharmaceutical University, Nanjing, China Search for more papers by this author Yingjie Nie Corresponding Author Yingjie Nie [email protected] orcid.org/0000-0002-8337-5304 NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non-profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003), Guizhou Provincial People's Hospital, Guiyang, China Search for more papers by this author Ning Li Corresponding Author Ning Li [email protected] orcid.org/0000-0002-3945-2536 Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Shuhang Wang Shuhang Wang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Kun Chen Kun Chen orcid.org/0000-0002-1855-5149 NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non-profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003), Guizhou Provincial People's Hospital, Guiyang, China Search for more papers by this author Qi Lei Qi Lei orcid.org/0000-0003-1953-9236 Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Peiwen Ma Peiwen Ma Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Andy Qingan Yuan Andy Qingan Yuan orcid.org/0000-0001-6200-2544 Excyte Biopharma Ltd, Beijing, China Excyte LLC, Rockville, MD, USA Search for more papers by this author Yong Zhao Yong Zhao Nanjing Umab-biopharma Co., Ltd, Nanjing, China Search for more papers by this author Youwei Jiang Youwei Jiang Hangzhou Genekine Biotech Co., Ltd, Hangzhou, China Search for more papers by this author Hong Fang Hong Fang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Shujun Xing Shujun Xing Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Yuan Fang Yuan Fang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Ning Jiang Ning Jiang Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Huilei Miao Huilei Miao Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Minghui Zhang Minghui Zhang Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China Search for more papers by this author Shujun Sun Shujun Sun Queen Mary School, Nanchang University, Nanchang, China Search for more papers by this author Zicheng Yu Zicheng Yu Geneplus, Shenzhen, China Search for more papers by this author Wei Tao Wei Tao China Pharmaceutical University, Nanjing, China Search for more papers by this author Qi Zhu Qi Zhu China Pharmaceutical University, Nanjing, China Search for more papers by this author Yingjie Nie Corresponding Author Yingjie Nie [email protected] orcid.org/0000-0002-8337-5304 NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non-profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003), Guizhou Provincial People's Hospital, Guiyang, China Search for more papers by this author Ning Li Corresponding Author Ning Li [email protected] orcid.org/0000-0002-3945-2536 Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China Search for more papers by this author Author Information Shuhang Wang1,†, Kun Chen2,†, Qi Lei1,†, Peiwen Ma1, Andy Qingan Yuan3,4, Yong Zhao5, Youwei Jiang6, Hong Fang1, Shujun Xing1, Yuan Fang1, Ning Jiang1, Huilei Miao1, Minghui Zhang7, Shujun Sun8, Zicheng Yu9, Wei Tao10, Qi Zhu10, Yingjie Nie *,2 and Ning Li *,1 1Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non-profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003), Guizhou Provincial People's Hospital, Guiyang, China 3Excyte Biopharma Ltd, Beijing, China 4Excyte LLC, Rockville, MD, USA 5Nanjing Umab-biopharma Co., Ltd, Nanjing, China 6Hangzhou Genekine Biotech Co., Ltd, Hangzhou, China 7Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China 8Queen Mary School, Nanchang University, Nanchang, China 9Geneplus, Shenzhen, China 10China Pharmaceutical University, Nanjing, China † These authors contributed equally to this work *Corresponding author. Tel: +86 13639043101; E-mail:[email protected] ***Corresponding author. Tel: +86 010 87788713; E-mail: [email protected] EMBO Mol Med (2021)13:e14291https://doi.org/10.15252/emmm.202114291 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Bispecific antibodies (bsAb) that target two independent epitopes or antigens have been extensively explored in translational and clinical studies since they were first developed in the 1960s. Many bsAbs are being tested in clinical trials for treating a variety of diseases, mostly cancer. Here, we provide an overview of various types of bsAbs in clinical studies and discuss their targets, safety profiles, and efficacy. We also highlight the current challenges, potential solutions, and future directions of bsAb development for cancer treatment. Glossary Monoclonal antibody (mAb) A mAb is made by cloning individual white blood cells and is specific for only one antigen or epitope. Monoclonal antibodies are widely used in cancer therapy to block cell growth, flag cancer cells for destruction, or trigger other mechanisms to kill cancer cells. Bispecific antibody (bsAb) A bsAb is designed to bind two different targets or epitopes and can thereby exert two different functions. They are currently used to treat infectious, inflammatory, and malignant diseases. Fragment crystallizable region (Fc) The Fc is the tail region of the immunoglobulin molecule, which contains only the constant region of the heavy chain and binds to effector molecules. T-cell receptor (TCR) TCR is a T-cell surface complex responsible for recognizing antigens and is stimulated by major histocompatibility complex molecules. T-cell-redirecting bispecific antibody (TRBA) TRBA is a bivalent antibody that binds to CD3 on T cells and a cancer cell antigen in order to recruit T cells to kill cancer cells. Bispecific T-cell engagers (BiTE) BiTE are a subtype of bispecific antibodies, which are constructed by connecting two single-chain variable fragments via a flexible linker. One fragment binds to a tumor-associated antigen, and the other binds to a T-cell-specific antigen to activate the T cell to kill the cancer cell to which it is linked. Dual-affinity re-targeting antibody (DART) DART consists of two variable fragments connecting the opposite heavy chain variable regions by a sulfide bond, which improves the stability. Tumor associate antigen (TAA) TAAs are antigens mainly arising from genetic amplification or post-translational modification that are expressed on tumor cells and a subset of normal cells. TAAs are usually expressed preferentially higher in tumor cells. Tumor-specific antigen (TSA) TSAs are antigens mainly arising from oncogenic driver mutations that generate novel peptide sequences. TSAs are only expressed on tumor cells and not present in normal cells. Cytokine release syndrome (CRS) CRS is a systemic inflammatory response triggered by infections, chemical drugs, or biological therapies. CRS is a serious adverse effect of T-cell-engaging immunotherapies such as bispecific antibodies and chimeric antigen receptor T-cell therapies. Definition and classification A bispecific antibody (bsAb) is designed and manufactured—through genetic recombination, chemical conjugation or quadromas—to contain two target-binding units in one antibody-based molecule, whereby each unit independently recognizes its unique epitope. Upon sequential or simultaneous binding, bsAb acts as a biophysical bridge between two antigens with multiple mode of actions (MoA) in vivo to achieve specific effects. Basic research and development have yielded many different forms of bsAb with different properties. Their classification can be based on various criteria, for example, the length of their half-life in vivo. Here, bsAbs can be roughly divided into two groups. The first one are small proteins, usually less than 50 kDa, generated by fusion of two basic single-chain variable fragment (scFvs) or two single-domain units. Termed bispecific T-cell engager (BiTEs; Löffler et al, 2000), dual-affinity re-targeting antibody (DARTs; Johnson et al, 2010), or diabodies (Holliger et al, 1996), they lack a human immunoglobulin constant region (Fc) which leads to quick clearance in vivo within a few hours. Accordingly, these smaller bsAbs have no Fc-mediated effector functions and require continuous administration for therapeutic use. The other group are long-lived bsAbs (> 150 KDa) with a half-life of up to several days in vivo. These include bsAbs with a human Fc and a classic antibody backbone similar to traditional IgG (Ridgway et al, 1996), and recent scFv-IgG fusion bispecific antibodies (Shen et al, 2006) or similar assemblies. The US FDA grouped bsAbs into two main classes based on their mechanism of action, namely cell-bridging bsAbs and antigen-crosslinking bsAbs (non-cell-bridging molecules; Labrijn et al, 2019). Most cell-bridging bsAbs are designed for cancer treatment by linking immune cells to malignant cells. Through sequential binding, that is, by binding the cancer cell first owing to a higher affinity to tumor antigens, cell-bridging bsAbs can improve specificity and effectiveness with reduced non-specific side effects and lower dosage compared with mAbs. In contrast, antigen-crosslinking bsAbs target two antigens or two receptors simultaneously. Their main MoA is either blocking signals of cell growth/survival or activation of immune cells (Engelman et al, 2007). Antigen-crosslinking bsAbs basically act similar to mAbs except that they bind two different targets. bsAbs have been used clinically in regenerative medicine and to treat infectious diseases such as HIV (Huang et al, 2016), hematological disorders, and cancer depending on their design and MoA. More than 85% of bsAbs in clinical trials are cancer therapeutics, of which more than 50% are cell-bridging bsAbs in small or large assembly formats (Fig 1). The basic anti-cancer bsAb construct usually recognizes a tumor-associated antigen (TAA) and either T cells usually via CD3 (Clark & Waldmann, 1987) or NK cells usually via CD16 (Oberg et al, 2018; Thakur et al, 2018). Figure 1. Schematic diagram of cell-bridging bispecific antibodies The basic bsAb construct is designed as two connected units, one specific to T cells (CD3) or NK cells (CD16) and the other to a tumor-associated antigen (TAA). In terms of in vivo half-life, bsAbs can be divided into two groups. Group one includes bsAbs small in size, typically consisting of two basic single-chain fragments with variable domain. The other group includes large and long-lasting bsAb with a full antibody backbone, structurally akin to classic IgG. (CH: heavy chain constant region, CL: light chain constant region, VH: heavy chain variable region, VL: light chain variable region, CK: cytokines). Download figure Download PowerPoint Overview of worldwide cancer-related bsAb clinical trials in the past 10 years Although the concept of bsAb was first proposed in 1964 (Nisonoff et al, 1960), its translation into clinical practice took several decades and had to address multiple problems in basic research and manufacturing. It was not until 2014 when the first product was approved: Blincyto, an anti-CD19 X anti-CD3 bispecific antibody (BiTE), gained FDA approval for treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (Przepiorka et al, 2015). Encouraged by the success of Blincyto, a considerable number of new clinical trials have been registered since 2014. Moreover, the number of new clinical trials evaluating novel bsAb drugs has been continuously increasing with an annual rate of 20.44% (Fig 2A). Of particular importance, a similar number of trials targeting solid tumors were observed compared with those targeting hematological malignancies (Fig 2B, solid tumors 170/308, 55.2% vs hematological tumors 138/308, 44.8%). Nonetheless, more than 93.5% of the trials are still in phase I or II. Figure 2. (A) History and phase distribution of bsAb clinical trials worldwide during the past ten years (2011-2020); (B) cancer types that bispecific antibodies are being used against Details of the trials were obtained from Pharmaprojects, a drug development database developed by INFORMA (https://pharma.id.informa.com). The following search keywords were used as follows: [(Therapeutic Class is Antiboby, bispecific, T cell engager) OR (Therapeutic Class is Antibody, bispecific)] AND (Actual Start Date is from 2010/01/01 to 2020/08/01)]. Download figure Download PowerPoint Here, we discuss the clinical characteristics and related details of bsAbs in clinical trials for cancer treatment between January 1, 2010, and August 1, 2020, based on data from Trialtrove and Pharmaprojects, a drug development database developed by INFORMA. In total, 308 projects investigating 126 bsAb drugs were analyzed. bsAbs for treating hematological tumors The 138 bsAb programs treating hematological tumors focused on 16 different targets, including CD19, CD20, BCMA, CD123, and CD33 (Fig 3A and B). Among them, more than half (73/138) were CD19-targeting cell-bridging bsAbs, probably trying to replicate the success of Blincyto. The second largest group targeting CD20, BCMA, and CD123 accounted for about one quarter of hematological cancer trials. The lion's share of bsAbs in these trials (129/133) redirected T cell (CD3) to cancer cells. Only five bsAb programs bridge NK cells by targeting CD30 and CD16. Antigen-crosslinking bsAbs accounted for just a tiny fraction (4/138). Figure 3. (A) Target combinations of bispecific antibodies in hematologic malignancies (combination of targets); (B) target combinations of bispecific antibodies in hematologic malignancies (number of antibodies) Details of the trials were obtained from Pharmaprojects, a drug development database developed by INFORMA (https://pharma.id.informa.com). The following search keywords were used as follows: [(Therapeutic Class is Antiboby, bispecific, T cell engager) OR (Therapeutic Class is Antibody, bispecific)] AND (Disease is Oncology: Unspecified Hematological Tumor) AND (Actual Start Date is from 2010/01/01 to 2020/08/01)]. Download figure Download PowerPoint Landscape of bsAb in treating solid tumors Solid tumors account for 90% of newly diagnosed cancer cases, but very few drugs are available to produce durable therapeutic benefits in patients, owing to the high heterogeneity of cancer cells, relatively low level of neoantigens on cancer cells, and the inhibitory tumor microenvironment. Notwithstanding, there are currently more than 170 clinical trials of bsAbs to treat solid tumors, targeting 56 molecules and/or their rational pairs (Fig 4A). Figure 4. (A) Target combinations of bispecific antibodies in solid tumors (combination of targets); (B) target combinations of bispecific antibodies in solid tumors (number of antibodies) Details of the trials were obtained from Pharmaprojects, a drug development database developed by INFORMA (https://pharma.id.informa.com). The following search keywords were used: [(Therapeutic Class is Antiboby, bispecific, T cell engager) OR (Therapeutic Class is Antibody, bispecific)] AND (Disease is Oncology: Unspecified Solid Tumor) AND (Actual Start Date is from 2010/01/01 to 2020/08/01)]. Download figure Download PowerPoint Compared to hematological cancer trials, bsAbs for treating solid tumors involve many more targets and multiple MoAs. While both immune cell-redirecting bsAbs and antigen-crosslinking bsAbs are being explored, the latter account for more than three fourth on these studies (99/135; Fig 4B). The crosslinked antigen pairs vary from single targets such as HER2/HER2 (biparatopic bsAb) to combinations of two different proteins, for example, VEGF/Ang-2, IGF-1/IGF-2, PD-1/CTLA4, PD-1/PD-L1, or PD-L1/CTLA4. Of note, many bsAbs (47/135 in Fig 4B) are being tested to target immune cells with the expectation that they outperform single mAbs (such as anti-PD-1 mAb) in modulating anti-cancer functions. The MoA of these bsAbs is mainly by targeting dual cell signaling pathways for enhanced inhibitory or stimulatory effects in malignant cells or immune cells accordingly. Immune cell-redirecting, anti-CD3/anti-TAA-based cell-bridging bsAbs on the other hand utilize not only tissue-specific tumor antigens (PSMA, GPC3, etc.) but also fewer specific antigens (HER2, EpCAM, CEA, etc.). Though some of the targets (HER2, EGFR, etc.) have been validated clinically, no bsAb drug against solid tumors has been approved to date. Nevertheless, a subgroup of cell-bridging bsAbs with CD3 as the constant target in T cells, termed TRBAs (T-cell-redirecting bispecific antibody), have begun to dominate novel cancer therapies from scientific research to clinical studies. Modes of actions of bsAb bsAbs are designed to achieve different functions through single or multiple MoAs: bridging tumor cells and immune cells for redirected cytotoxicity, blocking two targets to inhibit tumor growth, promoting immune cell functions, or facilitating the formation of protein complexes (Hemlibra, which is not the scope of this review). Bridging tumor cell and immune cells Cellular immune surveillance usually recognizes and eliminates abnormal cells by bridging them with a cytotoxic T cell via the TCR-MHC-peptide complex. Malignant cells may escape this link by lowering expression of immunological HLA peptide, in addition to secreting immune suppression molecules and creating a hostile tumor microenvironment for infiltrating T cells. The main aim of CD3- or CD16-targeting, TAA-based bsAbs is to create new and stable bridges between immune cells and tumor cells and thereby enhance the efficacy and coverage of T cell and NK cell action. Modulating the bridging strength may be key to optimizing clinical outcome. Blincyto, MGD011, and AFM11 were all designed to link T and B cells through CD3-CD19 bsAbs and had different cytokine release syndrome (CRS) profiles in clinical trials. Glofitamab, epcoritamab, and mosunetuzumab all are CD20×CD3 redirecting T cells to CD20-positive cells for treating B-cell malignancies by manipulating the bridging strength, in addition to modulating the affinities of the two moieties in a bsAb. Glofitamab was designed as a 2:1 antibody with two CD20 binding points and one CD3 binding point to achieve higher affinity against malignant cells and relatively lower affinity to immune cells to prevent massive immune activation and damage to normal tissues and cells. Epcoritamab designed with the DuoBody platform was subcutaneously administered with a better safety profile. In early-phase trials, there was no grade 3 CRS observed in patients treated with epcoritamab. Mosunetuzumab was a fully humanized IgG1-like bispecific antibody, investigated in R/R NHL and DLBCL, that produced a significant number of complete response among patients with acceptable safety profiles. NK cell can also be the effector in this type of bsAbs, by adopting the CD16 antibody, such as in AFM13 or GTB-3550. Blocking two targets Past conventional mAb therapeutics and small molecule drugs in oncology have unveiled one of the dominant resistance mechanisms by cancer cells: using alternative growth signals to compensate the blockade. Blocking two signal targets simultaneously, besides other antibody-mediated cytotoxicities, may overcome such resistance and enhance efficacy and coverage. This, however, requires careful design for bsAbs to balance the two antibody affinities to two targets as well as the spatial distance for sufficient and concurrent bivalent interaction. Amivantamab is such a bsAb that targets cMet and EGFR. It has been granted approval to treat non-small-cell lung cancer patients with resistant malignancies after several lines of tyrosine kinase inhibitors and patients with EGFRex20mut who lack other effective treatment. Amivantamab was investigated in patient subgroups with overall response rate (ORRs) greater than 30%. It effects multiple MoAs to inhibit tumor growth. First, dual inhibition of both EGFR and cMet signaling by blocking ligand-induced activation and inducing receptor degradation slows down tumor cell proliferation. Second, amivantamab has a low fucose N-glycosylation in Fc, which enhances Fc and FcgR interactions on NK cells, monocytes, and macrophages to harness antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. In addition, Fc–FcgR interaction can lead to antibody-dependent cellular trogocytosis, an antibody-mediated transfer of membrane fragments and ligands from tumor cells to effector cells such as monocytes, macrophages, and neutrophils. The induction of trogocytosis can also lead to down-regulation of EGFR and cMet receptors and their downstream signaling (Moores et al, 2016). bsAbs could also bind to different epitopes of one target to block one pathway more efficiently through enhanced receptor internalization. Such biparatopic bsAbs targeting HER2 (zenocutuzumab, KN026) are now in clinical trials, and more such targets, such as VEGF, VEGFR2, and DLL4, are being investigated for similar approaches. Activating immune cells T cells need to be carefully controlled during a defense action, and so-called immune checkpoints are such regulators that switch T-cell power on or off. Monoclonal antibodies against immune checkpoint regulators such as PD-1, PD-L1, or CTLA4 have been shown to display significant potencies in treating some cancers such as melanoma by activating T cells. However, they have limited effects in non-inflamed or cold tumors, and resistance has emerged after mAb monotherapy. Thus, bsAbs targeting two immune checkpoints simultaneously may synergize their immune-modulating functions. Moreover, monoclonal antibodies targeting co-stimulatory receptors, such as OX40, ICOS, or CD28, may cause strong systemic side effects: The mAb TGN1412 for instance caused several deaths in clinical trials. Their toxicity might be limited locally by developing bsAbs that co-target PD-L1, the expression of which is restricted around the tumor microenvironment. So far only two checkpoint-specific bsAbs are in phase 3 trials for treating solid tumors: KN046 (targeting PD-L1/CTLA4) and tebotelimab (targeting PD-1/LAG-3). Clinical progress of bsAb So far, there have been three bispecific antibodies approved by the FDA, two of them TRBA. Blincyto (Blinatumomab), bridging CD3 on T cells and CD19 on B cells, was first approved in 2014 for Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), based on a single-arm phase 2 trial that showed 33% complete response rate (NCT02000427), and then expanded to Ph+ patients and patients in remission with minimal residual disease in 2017 and 2018, respectively. Removab (Catumaxomab), bridging CD3 and EpCAM, was approved for malignant ascites in 2009 and withdrawn after 4 years owing to commercial reasons, immunogenicity and toxicity. The third bsAb, an oncology-unrelated product, Hemlibra (Emicizumab) was elegantly designed to prevent bleeding in hemophilia A patients and has been so far the most successful bsAb. It has changed the paradigm of hemophilia A treatment from three injections per week to once weekly or biweekly. There are a few other promising bsAbs with different structures in phase 3 clinical trials including IgG-like full-length antibodies, DARTs, and fusion proteins. A lot more entities are being investigated in early phases now and may enter phase 3 investigation within the next 5 years. Some antibodies in early-phase trials have been granted breakthrough therapy designation by FDA or enter other expedited programs (Table 1). Table 1. Bispecific antibodies investigated in late-phase clinical trials or granted expedited designations by FDA. Antibodies Targets Structure and platform Company Indication Pivotal trial(s) Trial phase FDA designation(s) Glofitamab (Bacac et al, 2018; Hutchings et al, 2021; Killock, 2021) CD3xCD20 Asymmetric (2 + 1) Roche DLBCL NCT04408638 3 BTD KN046 (Zhao et al, 2020) PD-L1xCTLA4 Asymmetric (1 + 1) Alphamab NSCLC NCT04474119 3 ·· ·· ·· ·· ·· Thymic carcinoma NCT04469725 2 Orphan IBI318 (Xu et al, 2020) PD-1xPD-L1 Asymmetric (1 + 1) Innovent NSCLC NCT04672928 1b/3
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