CD3-Bispecific Antibody Therapy: Comparison
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CD3-bispecific antibody therapy is a form of immunotherapy that enables soldier cells of the immune system to recognize and kill tumor cells.

  • antibody therapy
  • immuno-oncology
  • CD3-bispecific antibody

1. Introduction

CD3-bispecific antibodies (CD3-BsAbs) are an emerging treatment modality in the field of cancer immunotherapy. BsAbs can recognize distinct antigens with each of their antigen-binding domains, in contrast to conventional Abs that recognize the same antigen with both Fab arms. The exception is IgG4, which has been reported to naturally exchange arms to attain bispecificity [1]. CD3-BsAbs act by simultaneous binding to a tumor-associated antigen (TAA) expressed on tumor cells and to CD3 on a T cell (CD3xTAA) [2]. Crosslinking of these two cell types by CD3-BsAbs allows the formation of an immunological synapse, similar to that of a natural T-cell receptor (TCR)/peptide–major histocompatibility complex (MHC) complex [3]. This synapse results in T-cell activation and thereby the secretion of inflammatory cytokines and cytolytic molecules that are able to kill the tumor cells in the process. The strength of CD3-BsAbs lies in the fact that any T cell could serve as an effector cell, regardless of TCR specificity, as for these BsAbs, TCR signaling does not require engagement of the antigen-binding domain of the TCR, but is initiated via CD3 [4]. Therefore, CD3-BsAbs can employ all available T cells and are not limited to tumor-specific T cells, contrary to the key requirement for effective immune checkpoint therapy [5].

CD3-BsAb therapy is a passive form of immunotherapy and shows striking kinship with the adoptive cell transfer of T cells expressing chimeric antigen receptor (CAR) transgenes [6]. CARs consist of TAA binding domains from antibodies directly linked to the intracellular CD3ζ chain and domains from costimulatory receptors (e.g., 4-1BB) and thereby activate T cells upon antigen recognition. CD3-BsAbs and CAR T cells are similar in many ways: both target a surface TAA, both exploit T-cell effector functions and both are successfully used in the clinic for hematological malignancies and show a similar type of toxicity profile [7][8]. Some disadvantages of currently clinically approved CAR T cells compared to CD3-BsAbs are: (1) patients are required to be lymphodepleted prior to infusion of CAR T cells, (2) CAR T cells have to be individually produced for each patient, whereas CD3-BsAbs can serve as off-the-shelf therapeutics, (3) CAR T cells remain in the patients after the tumor is cleared, resulting in continuous B-cell depletion in the case of CD19-targeting CAR T cells, whereas CD3-BsAbs are cleared from the blood over time and (4) unlike CD3-BsAbs, dosing cannot be adjusted to minimize adverse events [7][9]. Nevertheless, it will be important to learn from the CAR T cell field to potentially extrapolate new findings to the CD3-BsAb field.

Over the last few years, new insights in BsAb biology and enabling technologies resulted in the generation of many different formats of CD3-BsAbs, which was elaborately reviewed by Labrijn et al. [10]. As of December 2020, over 100 different CD3-BsAb formats are known, ranging from very small fragments containing two different variable domains without an Fc tail, conventional antibody structures (two Fab arms linked to an Fc tail) and larger structures with additional variable domains linked to the conventional antibody structure. These different formats determine important features, such as antibody half-life via neonatal Fc receptor (FcRn)-mediated recycling, immunogenicity, type of effector response via altered immune synapse formation and ability to penetrate in solid tumors [11]. The presence and functionality of the Fc tail determines whether the BsAb is able to bind to and activate Fc receptor (FcR)-expressing immune cells, which could lead to stronger inflammatory responses, but also allows activation of immune cells in the absence of TAA, potentially resulting in more severe adverse events (AEs) [12].

Currently, CD3-BsAbs show great potential for hematological cancers, with the FDA-approved blinatumomab (CD3xCD19) being successfully used in the clinic to treat some B-cell malignancies. Many other CD3-BsAbs are being tested in (pre)clinical studies for both hematological and solid tumors. However, contrary to the success of CD3-BsAbs in hematological malignancies, the effect of these antibodies in solid tumors is still rather limited [13].

2. CD3-BsAbs in Hematological Malignancies

CD3-BsAbs received a lot of attention due to their success in hematological cancers. Blinatumomab (a CD3xCD19 BsAb without an Fc tail) was FDA approved in 2014 and is now successfully used in the clinic to treat patients suffering from relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) [14]. Over 40% of adult patients treated with blinatumomab show a complete or partial response and median overall survival is improved by several months compared to standard of care chemotherapy [15][16][17]. Unfortunately, most patients still relapse eventually after primary response to blinatumomab therapy. These relapses are currently being extensively investigated and the data have thus far indicated that relapses are frequently found at immune-privileged extramedullary locations and some relapses have lost CD19 antigen expression, but more research is required to further elucidate these resistance mechanisms [18][19].

Apart from blinatumomab, many other CD3-BsAbs are currently in clinical trials targeting well-established B-cell markers, like CD19, CD20, CD38 and B-cell maturation antigen (BCMA) and myeloid markers, like CD33 and CD123. For instance, in a phase I/II study, patients suffering from acute myeloid leukemia (AML) were treated with flotetuzumab (CD3xCD123 BsAb) and showed promising overall response rates (complete response with full, partial or incomplete recovery of blood cells) of 30% [20]. In another phase I/II study for patients suffering from diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL) or follicular lymphoma (FL), epcoritamab (CD3xCD20 BsAb) therapy generated impressive responses: 44% complete response (CR) and 11% partial response (PR) for patients with DLBCL or HGBCL and 100% PR for patients with FL [21]. Comparable results were obtained with other CD3xCD20 bispecifics [22][23]. In NOD/SCID-gamma null (NSG) mice, REGN1979 (CD3xCD20) delayed tumor outgrowth better than rituximab, thereby further indicating the strength of CD3-BsAbs [24]. Interestingly, some of these trials target the same B-cell or myeloid antigens, however, with different CD3-BsAb formats. Therefore, these clinical studies could potentially inform on the role of different antibody formats’ treatment safety and efficacy.

Clinical trials with blinatumomab revealed that cytokine release syndrome (CRS) is one of the major safety-related AEs [25]. The availability of CD19+ tumor cells and healthy B- and T cells in the same compartment allows acute and synchronic CD3-BsAb-mediated T-cell activation, followed by excessive release of inflammatory cytokines, such as IFN-γ, IL-6 and TNF-α, resulting in symptoms ranging from mild fever to multi-organ system failure [26]. However, CRS is not a specific problem for blinatumomab, but is observed for all CD3-BsAbs and CAR T-cell therapies in both hematological and solid cancer indications with CRS severities dependent on the type of therapy and target [27][28]. Preclinical research using a humanized mouse model showed that the primary mediator of CD3-BsAb-induced CRS was TNF-α produced by activated T cells, leading to massive secretion of inflammatory cytokines by monocytes [29]. The blockade of upstream TNF-α and downstream IL-1β or IL-6 can mitigate CRS [29][30][31]. Others have reported that step-up dosing, or subcutaneous administration of CD3-BsAbs, decreased the extent of CRS [32][33]. Furthermore, several preclinical studies in mouse and cynomolgus monkey models showed that reducing CD3 affinity could reduce treatment-induced cytokine levels [34][35][36][37].

3. Historical Perspective and Current Status of CD3-BsAbs in Solid Cancers

Despite the fact that CD3-BsAbs are mostly known for their use in hematological malignancies, the first European medicines agency (EMA)-approved CD3 bispecific antibody was catumaxomab, a CD3xEpCAM BsAb for the intraperitoneal treatment of epithelial cell adhesion molecule (EpCAM)-positive malignant ascites [38]. This antibody was actually trifunctional, as its Fc was able to bind FcR-expressing cells and induced strong immunological responses [39]. Severe liver toxicity was also observed due to the activation of Kupffer cells when administered intravenously [12]. Catumaxomab was eventually withdrawn for commercial reasons in 2017, but taught the field an important lesson about the potential dangers of the presence of an active Fc in CD3-BsAbs. All current full length CD3-BsAbs in development contain Fc-silent backbones with mutations impairing the binding of FcγR and C1q [10]. Moreover, preclinical studies showed that Fc-silenced full length CD3-BsAbs improved T-cell trafficking towards the tumor and induced better anti-tumor responses. Wang et al. showed that CD3-BsAbs with an active Fc backbone failed to drive T cells to the tumor, but instead induced either T-cell depletion or the accumulation of T cells in the lungs [40]. This observed effect was attributed to the capacity of the Fc backbone to be bound by FcγR-expressing myeloid cells. Fc-silenced CD3-BsAbs did not lead to sequestration of T cells in the lungs, but they arrived in the tumor. More importantly, therapeutic efficacy was greatly improved in Fc-silenced CD3-BsAb-treated mice. A similar trend was also observed in a syngeneic mouse model, where CD3xTrp1 (tyrosinase-related protein 1) was used to treat Trp1-positive B16F10 tumor cells [41].

As of December 2020, no CD3-BsAbs are approved for the treatment of solid tumors in the clinic. However, many different targets are being explored in clinical studies, of which most are focusing on classical TAAs, such as carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EpCAM, HER2 and prostate-specific membrane antigen (PSMA). Other TAAs are also being explored (see Table 1 for an elaborate list). Most of these studies simply inject CD3-BsAbs, however, in some studies, these Abs piggyback with infused T cells as “bispecific-armed T cells”. Furthermore, this table also includes CD3-BsAb formats based on affinity-enhanced TCR-like domains that recognize peptide–human leukocyte antigen (HLA) complexes (immune mobilizing monoclonal T-cell receptors against cancer (ImmTACs)) [42]. Multiple other TAAs are currently pursued in preclinical studies hoping to make their way to the clinic, including B7-H4, CD133, CD155, claudin 6 (CLDN6), cellular mesenchymal to epithelial transcription factor (C-MET), ephrin receptor A10 (EphA10), folate receptor 1 (FOLR1), HLA-A*24:survivin 2B80-88, integrin β4 (ITGB4), P-cadherin, prolactin receptor (PRLR), receptor tyrosine kinase-like orphan receptor 1 (ROR1), TNF-related apoptosis-inducing ligand receptor (TRAIL-R2), transferrin receptor (TfR) and tumor-associated calcium signal transducer 2 (Trop-2) [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69].

Table 1. Overview of clinical studies involving CD3-BsAbs targeting solid tumors.

TAA Disease Phase
Completed Clinical Trials
CEA CEA-positive tumors Phase I (NCT02324257, completed)
CEA Gastrointestinal adenocarcinomas Phase I NCT01284231, completed)
CEA Advanced CEA-positive solid tumors Phase I (NCT02291614, completed)
CEA Advanced CEA-positive solid tumors Phase I (NCT02650713, completed)
EGFR Brain and central nervous system tumors Phase I (NCT00005813, completed)
EpCAM Solid tumors Phase I (NCT00635596, completed)
EpCAM Ascites, ovarian cancer, fallopian tube cancer, peritoneal cancer Phase II (NCT00326885, completed)
EpCAM Ovarian cancer, fallopian tube cancer, peritoneal cancer Phase II (NCT00377429, completed)
EpCAM Recurrent ovarian cancer, fallopian tube cancer, peritoneal carcinomatosis Phase II (NCT01815528, completed)
EpCAM Ovarian cancer, fallopian tube cancer, peritoneal cancer Phase II (NCT01246440, completed)
EpCAM Ovarian cancer Phase II (NCT00563836, completed)
EpCAM Ascites, carcinoma, epithelial cancer Phase II (NCT01065246, completed)
EpCAM Ovarian cancer, gastric cancer, pancreatic cancer, malignant ascites Phase II (2005-001700-39, completed)
EpCAM Gastric cancer and gastric adenocarcinoma Phase II (NCT00352833, completed)
EpCAM Peritoneal carcinomatosis and gastric adenocarcinoma Phase II (NCT01504256, completed)
EpCAM Ovarian cancer, fallopian tube cancer, peritoneal cancer Phase II (NCT00189345, completed)
EpCAM Gastric cancer and gastric adenocarcinoma Phase II (NCT00464893, completed)
EpCAM Malignant ascites and EpCAM-positive tumors Phase II/III, (NCT00836654, completed)
EpCAM EpCAM-positive solid cancers Phase III (NCT00822809, completed)
GD2 Neuroblastoma Phase I (NCT00877110, completed)
gpA33 Colorectal carcinoma Phase I (NCT02248805, completed)
GPC3 Solid tumors Phase I (NCT02748837, completed)
HER2 Breast cancer, metastatic breast cancer Phase I (NCT00027807, completed)
HLA-A*02:01:gp100 Melanoma, advanced melanoma Phase I (NCT01209676, completed)
HLA-A*02:01:gp100 Malignant melanoma Phase I (NCT01211262, completed)
PSMA Prostate cancer Phase I (NCT02262910, completed)
PSMA Prostatic neoplasms Phase I (NCT01723475, completed)
Active clinical trials *
5T4 Malignant solid tumors Phase I/II (NCT04424641, recruiting)
B7-H3 Advanced solid tumors, metastatic solid tumors Phase I (NCT03406949, active not recruiting)
CEA Colorectal cancers Phase I (NCT03866239, recruiting)
CEA NSCLC Phase I/II (NCT03337698, recruiting)
CEA, EGFR, GPC3, HER2, MUC1 Malignant solid tumors Phase I (NCT04076137, recruiting)
CEA, EpCAM, GPC3, MUC1 Advanced liver cancer Phase II (NCT03146637, recruiting)
CLDN18.2 Gastric and gastroesophageal junction adenocarcinoma Phase I (NCT04260191, recruiting)
DLL3 Small cell lung carcinoma Phase I (NCT03319940, recruiting)
DLL3 Small cell lung cancer, advanced cancers Phase I/II (NCT04471727, not yet recruiting)
EGFR Multiple solid gastrointestinal tumors Phase I (NCT01420874, active not recruiting)
EGFR Glioblastoma multiforme, gliosarcoma Phase I (NCT03344250, recruiting)
EGFR Pancreatic cancer Phase I (NCT04137536, recruiting)
EGFR Advanced pancreatic cancer Phase Ib/II (NCT02620865, active not recruiting)
EGFR Advanced and metastatic pancreatic adenocarcinoma Phase Ib/II (NCT03269526, recruiting)
EGFRv3 Glioblastoma multiforme, malignant glioma Phase I (NCT03296696, active not recruiting)
EpCAM Large bowel (colon) cancer, colorectal cancer Phase U (ChiCTR-ROC-16008620, not yet recruiting)
EpCAM Malignant ascites, advanced solid tumors Phase I (CTR20181212, recruiting)
EpCAM Ascites, advanced solid tumors Phase I (ChiCTR1900024144, recruiting)
EpCAM Malignant ascites Phase I (NCT04501744, recruiting)
EpCAM Gastric adenocarcinoma, peritoneal carcinomatosis, colorectal adenocarcinoma Phase II (2010-022810-26, recruiting)
EpCAM Advanced gastric cancer, stomach cancer, gastric cancer Phase III (NCT04222114, recruiting)
GD2 Neuroblastoma Phase I (NCT02650648, active not recruiting)
GD2 Neuroblastoma, osteosarcoma, other solid tumors Phase I/II (NCT03860207, recruiting)
GD2 Neuroblastoma, osteosarcoma Phase I/II (NCT02173093, recruiting)
gpA33 Metastatic colorectal cancer Phase I/II (NCT03531632, active not recruiting)
GPC3 Advanced solid tumors, recurrent solid tumors Phase I (JapicCTI-194805, recruiting)
GUCY2C Gastrointestinal malignancies, esophageal cancer Phase I (NCT04171141, recruiting)
HER2 Breast cancer Phase U (ChiCTR-ROC-16008650, not yet recruiting)
HER2 HER2-positive solid tumors Phase I (NCT04501770, recruiting)
HER2 Breast cancer and leptomeningeal metastases Phase I (NCT03661424, recruiting)
HER2 Esophageal, gastric, pancreatic, liver, gallbladder and bowel cancer Phase I (NCT02662348, unknown status)
HER2 Advanced solid tumors Phase I (NCT03448042, recruiting)
HER2 Advanced solid tumors Phase I (CTR20171194, recruiting)
HER2 Solid tumors, advanced solid tumors Phase I (ChiCTR1900024128, recruiting)
HER2 Breast cancer Phase I/II (NCT03983395, recruiting)
HER2 Metastatic breast cancer Phase I/II NCT03272334, recruiting)
HER2 Metastatic castration resistant prostate cancer Phase II (NCT03406858, status unknown)
HER2 Breast cancer Phase II (NCT01147016, status unknown)
HER2 Breast cancer Phase II (NCT01022138, status unknown)
HLA-A*02:01:gp100 Uveal melanoma Phase I/II (NCT02570308, active not recruiting)
HLA-A*02:01:gp100 Melanoma Phase I/II (NCT02535078, active not recruiting)
HLA-A*02:01:gp100 Uveal melanoma, metastatic uveal melanoma, advanced uveal melanoma Phase II (NCT03070392, active not recruiting)
HLA-A*02:MAGE-A4 Advanced solid tumors, metastatic solid tumors Phase I/II (NCT03973333, recruiting)
MSLN Mesotheliomas, ovarian cancers, pancreatic cancers Phase I/II (NCT03872206, recruiting)
MUC16 Ovarian cancer fallopian tube cancer, peritoneal cancer Phase I/II (NCT04590326, not yet recruiting)
MUC16 Ovarian cancer fallopian tube cancer, peritoneal cancer Phase I/II, (NCT03564340, recruiting)
MUC17 Gastric and gastroesophageal junction cancer Phase I (NCT04117958, recruiting)
NY-ESO1 NY-ESO1-positive tumors Phase I/II (NCT03515551, recruiting)
PRAME Advanced solid tumors, cancer indications Phase I/II (NCT04262466, recruiting)
PSCA NSCLC, breast cancer, pancreatic cancer, urogenital cancer Phase I NCT(03927573, recruiting)
PSMA Prostate cancer Phase I (NCT04077021, recruiting)
PSMA Prostate cancers, advanced solid tumors, neoplasms, renal cancers, small cell lung cancer Phase I (NCT03926013, recruiting)
PSMA Castration-resistant prostate carcinoma Phase I (NCT04104607, recruiting)
PSMA Metastatic castration-resistant prostate cancer Phase I (NCT03792841, recruiting)
PSMA Squamous cell lung carcinoma Phase I/II NCT04496674, not yet recruiting)
PSMA Prostate cancer Phase I/II (NCT03577028, recruiting)
SSTR2 Neuroendocrine tumors and gastrointestinal neoplasms Phase I (NCT03411915, recruiting)
SSTR2 Merkel cell carcinoma and small cell lung cancer Phase I/II (NCT04590781, not yet recruiting)
STEAP1 Metastatic castration-resistant prostate cancer Phase I (NCT04221542, recruiting)

* Data as of 13 November 2020. Clinical studies are ordered based on the targeted tumor-associated antigen (TAA). CEA, carcinoembryonic antigen; CLDN18.2, claudin18 isoform 2; DLL3, delta-like ligand 3; EGFR, epidermal growth factor receptor, EpCAM, epithelial cell adhesion molecule; GD2, disialoganglioside; gp100, glycoprotein 100; gpA33, glycoprotein A33; GPC3, glypican 3; GUCY2C, guanylyl cyclase C; HER2, human epidermal growth factor receptor 2; HLA, human leukocyte antigen; MAGE-A4, melanoma-associated antigen 4; MSLN, mesothelin, MUC16, mucin 16; NSCLC, non-small cell lung cancer; NY-ESO1, New York esophageal squamous cell carcinoma 1; PRAME, preferentially expressed antigen in melanoma; PSCA, prostate stem cell antigen; PSMA, prostate-specific membrane antigen; SSTR2, somostatin receptor 2; STEAP1, six-transmembrane epithelial antigen of the prostate 1.

Most of these studies are currently still enrolling patients and we are only starting to get a view on CD3-BsAb therapy safety and efficacy in solid cancers. First, in three different studies, patients were treated with an i.p. infusion of catumaxomab, which resulted in frequent but manageable toxicities and increased time between paracentesis in all studies and even a significant improvement in overall survival (OS) in one study [38,70,71]. Other clinical trials in solid tumors reported dose-limiting toxicities (DLTs) for CD3-BsAbs targeting CEA, EpCAM and HLA-A*02:01:gp100 [70,71,72,73]. These toxicities consisted of abnormal liver parameters, colitis, CRS, diarrhea, dyspnea, hypotension, hypoxia, respiratory failure and tachycardia. Some of these toxicities were caused by tumor lesion inflammation, however, most were reversible upon treatment discontinuation. Responses to CD3-BsAbs varied from only 1.5% partial response (PR) [70], up to 15% PR and 46% stable disease (SD) [73] and everything in between [73,74,75]. Pasotuxizumab, a CD3-BsAb targeting PSMA, obtained the most impressive results with two long-term responders, of which one had marked regression of soft tissue and bone metastases [74]. Overall, some evidence for efficacy induced by CD3-BsAbs in solid tumors has been found, however, with only a handful of long-term survivors, some partial responses and the occurrence of multiple DLTs, the development of CD3-BsAbs in solid tumors lags behind that in hematological malignancies.

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