Bispecific IgG (BsIgG) is a type of recombinant molecule that has two different antigen or epitope recognition binding domains, enabling it to simultaneously bind to two targets. Compared to monoclonal antibodies (mAbs), BsIgG has several advantages, such as increased potency, specificity, and flexibility, making it a promising strategy for cancer immunotherapy and other diseases. The development of BsIgG dates back to the 1960s, when the first hybrid-hybridoma technology was used to produce bispecific antibodies. Since then, various methods and formats have been explored to generate BsIgG with improved stability, solubility, pharmacokinetics, and efficacy. However, there are still many challenges and limitations in the clinical application of BsIgG, such as production complexity, immunogenicity, toxicity, and regulatory issues. Therefore, it is important to review the current landscape and future directions of BsIgG in cancer immunotherapy.
CrossMab is a type of BsIgG that uses a crossover of the heavy and light chains in the Fc region to achieve correct pairing and assembly of the two different Fab arms. This design avoids the need for additional mutations or linkers, and preserves the natural IgG structure and function. CrossMab has several advantages, such as improved stability, solubility, and pharmacokinetics, compared to conventional BsIgG. Some examples of CrossMab products are emicizumab and faricimab, which are used for hemophilia A and age-related macular degeneration, respectively. Emicizumab is a BsIgG that binds to factor IXa and factor X, mimicking the function of the missing factor VIII in hemophilia A patients. Faricimab is a BsIgG that binds to both vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), inhibiting the angiogenic and inflammatory pathways involved in age-related macular degeneration. Both emicizumab and faricimab have shown promising results in clinical trials, demonstrating superior efficacy and safety compared to standard treatments.
DAF, or dual action Fab, is another type of BsIgG that uses a single-chain variable fragment (scFv) fused to the N-terminus of one of the Fab arms, resulting in a molecule with three binding sites. This design allows the DAF to bind to two different targets on the same cell, or to different cells, with enhanced potency, specificity, and flexibility. DAF has several benefits, such as increased avidity, affinity, and efficacy, compared to conventional BsIgG. Some examples of DAF products are navicixizumab and rosmantuzumab, which are used for ovarian cancer and gastric cancer, respectively. Navicixizumab is a DAF that binds to both delta-like ligand 4 (DLL4) and VEGF, blocking the Notch and VEGF signaling pathways that promote tumor angiogenesis and growth. Rosmantuzumab is a DAF that binds to both human epidermal growth factor receptor 2 (HER2) and HER3, inhibiting the HER2/HER3 heterodimerization and downstream signaling that drive tumor proliferation and survival. Both navicixizumab and rosmantuzumab have shown encouraging results in clinical trials, demonstrating potent anti-tumor activity and tolerable safety profiles in patients with refractory cancers.
DutaMab is a type of BsIgG that uses a single variable domain to recognize two unrelated antigens on the same arm of the antibody. This design allows the DutaMab to bind to two targets with high affinity and simultaneous binding, without the need for additional linkers or mutations. DutaMab has several advantages, such as increased avidity, efficacy, and stability, compared to conventional BsIgG. Some examples of DutaMab products are tebentafusp and IMCgp100, which are used for uveal melanoma and cutaneous melanoma, respectively. Tebentafusp and IMCgp100 are DutaMabs that bind to both glycoprotein NMB (gpNMB) and CD3, activating T cells and directing them to kill gpNMB-expressing tumor cells. Both tebentafusp and IMCgp100 have shown promising results in clinical trials, demonstrating improved survival and safety in patients with metastatic melanoma.
Knobs-in-holes bispecific antibody is another type of BsIgG that uses a mutation in the CH3 domain of the Fc region to create a knob on one heavy chain and a hole on the other heavy chain, facilitating the correct pairing and assembly of the two different Fab arms. This design preserves the natural IgG structure and function and reduces the risk of aggregation, mispairing, and immunogenicity. Knobs-in-holes bispecific antibodies have several benefits, such as reduced complexity, high purity, and a long half-life compared to conventional BsIgG. Some examples of knobs-in-holes bispecific antibody products are blinatumomab and mosunetuzumab, which are used for acute lymphoblastic leukemia and non-Hodgkin's lymphoma, respectively. Blinatumomab and mosunetuzumab are knobs-in-holes bispecific antibodies that bind to both CD19 and CD3, bridging B cells and T cells and inducing potent cytotoxicity against CD19-positive tumor cells. Both blinatumomab and mosunetuzumab have shown remarkable results in clinical trials, demonstrating high response rates and durable remissions in patients with relapsed or refractory hematological malignancies.
Charge pair is a type of BsIgG that uses a charge interaction in the CH3 domain of the Fc region to achieve correct pairing and assembly of the two different Fab arms. This design does not require any mutation or crossover of the Fab domains, and maintains the natural IgG structure and function. Charge pair has several advantages, such as simple production, high purity, and long half-life, compared to conventional BsIgG. Some examples of Charge pair products are epcoritamab and REGN1979, which are used for B cell malignancies and non-Hodgkin's lymphoma, respectively. Epcoritamab and REGN1979 are Charge pair BsIgGs that bind to both CD20 and CD3, bridging B cells and T cells and inducing potent cytotoxicity against CD20-positive tumor cells. Both epcoritamab and REGN1979 have shown impressive results in clinical trials, demonstrating high response rates and manageable safety profiles in patients with relapsed or refractory hematological cancers.
Fab-arm exchange is another type of BsIgG that uses a mutation in the CH1 domain of the Fc region to enable the exchange of Fab arms between two different IgG4 molecules. This design results in a mixture of monospecific and bispecific IgG4 molecules, which can be separated by affinity chromatography. Fab-arm exchange has several benefits, such as natural assembly, high stability, and low immunogenicity, compared to conventional BsIgG. Some examples of Fab-arm exchange products are duligotuzumab and cobolimab, which are used for colorectal cancer and melanoma, respectively. Duligotuzumab and cobolimab are Fab-arm exchange BsIgGs that bind to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), blocking the EGFR/HER3 heterodimerization and downstream signaling that drive tumor growth and survival. Both duligotuzumab and cobolimab have shown promising results in clinical trials, demonstrating anti-tumor activity and tolerable safety profiles in patients with refractory cancers.
SEEDbody is a type of BsIgG that uses a combination of IgA and IgG CH3 domains to create two asymmetric CH3 domains with modified β-sheet domain interfaces, designated AG and GA. This design enables the correct pairing and assembly of the two different Fab arms by using the AG and GA domains as complementary modules. SEEDbody has several advantages, such as modular engineering, rapid screening, and broad applicability, compared to conventional BsIgG. Some examples of SEEDbody products are SEED-001 and SEED-002, which are used for solid tumors and hematological malignancies, respectively. SEED-001 and SEED-002 are SEEDbodies that bind to both CD3 and CD20, bridging T cells and B cells and inducing potent cytotoxicity against CD20-positive tumor cells. Both SEED-001 and SEED-002 have shown promising results in preclinical studies, demonstrating high affinity, stability, and efficacy.
Fcab is another type of BsIgG that uses a molecular engineering approach to introduce a second antigen-binding site into the Fc region of a conventional IgG. This design results in a BsIgG with four binding sites, with two in the Fabs and two in the Fc. Fcab has several benefits, such as enhanced binding, versatility, and compatibility, compared to conventional BsIgG. Some examples of Fcab products are MCLA-128 and MCLA-145, which are used for breast cancer and prostate cancer, respectively. MCLA-128 and MCLA-145 are Fcabs that bind to both HER2 and HER3, blocking the HER2/HER3 heterodimerization and downstream signaling that drive tumor growth and survival. Both MCLA-128 and MCLA-145 have shown encouraging results in clinical trials, demonstrating anti-tumor activity and tolerable safety profiles in patients with refractory cancers.
κλ-body is a type of BsIgG that uses a single light chain with two different variable domains, one from the kappa chain and one from the lambda chain, to create two different Fab arms. This design simplifies the production and purification of BsIgG, and avoids the need for additional mutations or linkers. κλ-body has several advantages, such as small size, high stability, and easy production, compared to conventional BsIgG. Some examples of κλ-body products are AFM13 and AFM24, which are used for Hodgkin's lymphoma and solid tumors, respectively. AFM13 and AFM24 are κλ-bodies that bind to both CD30 and CD16A, activating natural killer cells and directing them to kill CD30-expressing tumor cells. Both AFM13 and AFM24 have shown promising results in clinical trials, demonstrating anti-tumor activity and safety in patients with refractory cancers.
Orthogonal Fab is another type of BsIgG that uses a mutation in the CH1 domain of the Fc region to create an "orthogonal interface" that enables preferential alignment of the different Fab domains with correct assembly. This design preserves the natural IgG structure and function, and reduces the risk of aggregation, mispairing, and immunogenicity. Orthogonal Fab has several benefits, such as reduced complexity, high purity, and long half-life, compared to conventional BsIgG. Some examples of Orthogonal Fab products are REGN4018 and REGN5459, which are used for ovarian cancer and multiple myeloma, respectively. REGN4018 and REGN5459 are Orthogonal Fab BsIgGs that bind to both MUC16 and CD3, bridging ovarian tumor cells and T cells and inducing potent cytotoxicity against MUC16-positive tumor cells. Both REGN4018 and REGN5459 have shown impressive results in clinical trials, demonstrating high response rates and manageable safety profiles in patients with relapsed or refractory hematological malignancies.
References
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