Multispecific anti-TCR delta variable domain 1 antibody

Abstract

The present invention provides multispecific antibodies comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site specific for an epitope of the variable δ1 (Vδ1) chain of the γδ T cell receptor (TCR) and the Fc region comprises an EGFR binding site. The present invention also provides compositions and pharmaceutical compositions comprising such multispecific antibodies, as well as methods of making such multispecific antibodies. The present invention also provides methods of treatment and medical uses using the multispecific antibodies.

Description

[Technical Field]

[0001] The present invention relates to multispecific antibodies that specifically bind to the T cell receptor of γδ T cells and specifically bind to EGFR, as well as fragments and variants thereof. [Background technology]

[0002] Growing interest in T cell immunotherapy for cancer has focused on the apparent ability of CD8+ and CD4+ αβ T cell subsets to recognize cancer cells and mediate host-protective functions, particularly when derepressed by clinically relevant antagonism of inhibitory pathways exerted by PD-1, CTLA-4, and other receptors. However, αβ T cells are MHC-restricted, which can lead to graft-versus-host disease.

[0003] Gamma delta T cells (γδ T cells) are a subset of T cells that express a distinct, distinctive γδ T cell receptor (TCR) on their surface. This TCR is composed of one gamma (γ) chain and one delta (δ) chain, each of which undergoes chain rearrangement. However, compared to αβ T cells, these cells have a limited number of V genes. The main TRGV gene segments encoding Vγ are TRGV2, TRGV3, TRGV4, TRGV5, TRGV8, TRGV9, and TRGV11, as well as nonfunctional genes TRGV10, TRGV11, TRGVA, and TRGVB. The most common TRGV gene segments encode Vδ1, Vδ2, and Vδ3, with several V segments designated both Vδ and Vα (Adams et al., 2015, Cell Immunol., 296:30-40). Human γδ T cells can be broadly classified based on their TCR chain, as particular γ and δ types are widely, but not exclusively, found in cells of one or more tissue types. For example, most blood-resident γδ T cells express Vδ2 TCRs, commonly Vγ9Vδ2, whereas this is less common in tissue-resident γδ T cells, e.g., those in the skin, which more frequently use Vδ1 TCRs paired with a γ chain, e.g., Vδ1 TCRs paired with Vγ4 in the gut.

[0004] γδ T cells play a key role in immune surveillance, recognizing malignant or transformed cells (such as cancer cells) by their stress marker patterns and then exerting potent and selective cytotoxicity. Thus, γδ T cells can act as orchestrators of the immune response. In situ modulation of these cells offers the potential for increased immunogenicity, even in tumors with low mutational burdens, which have proven challenging for other immunotherapies. γδ T cell recognition of tumors is not dependent on any single tumor antigen; therefore, modulators of γδ T cells have potential in a wide range of disease indications, including both hematological and solid malignancies. The recognition mechanism of γδ T cells is not MHC-restricted.

[0005] The authors of WO2019147735 hypothesize that some gamma delta cells have tumor-promoting activity or inhibit anti-cancer immune responses mediated by alpha beta T cells. They hypothesize that gamma delta T cells are immunosuppressants and therefore propose that they should be eliminated, inhibited, or blocked using antibodies in cancer.

[0006] However, despite the prevailing view that anti-γδ antibodies negatively regulate the function of γδ cells by blocking or killing such cells, a positive correlation has been found between γδ T cell infiltration and patient prognosis and / or survival.

[0007] Compared to the αβ TCR receptor / ligand interaction, our understanding of the vδ1 TCR receptor / ligand interaction is limited. Due to this lack of understanding, antibodies recognizing the vδ1 TCR to date have primarily been exploratory tools for investigating this interaction. Typically, these tools are crude blocking antibodies that suggest that the TCR receptor / ligand interaction results in the blocking, suppression, or elimination of vδ1+ cells. For example, the tool antibodies TS8.2 and TS-1 have been used as anti-γδ blocking antibodies in studies suggesting that they reduce the cytotoxicity of vδ1 cells. These studies, combined with others, suggest that such anti-vδ1 antibodies cannot be used to favorably modulate vδ1 cell cytotoxicity in in situ disease, thus suggesting the need for antibodies that increase, rather than decrease, vδ1 cytotoxicity.

[0008] To utilize γδ T cells for immunotherapy, either a means to expand the cells in situ or a means to harvest and expand them ex vivo before reinfusion is required. The latter approach, which utilizes the addition of exogenous cytokines, has been previously described. See, for example, WO2017 / 072367 and WO2018 / 212808. Methods for expanding a patient's own γδ T cells using pharmacologically modified forms of hydroxymethylbut-2-enyl pyrophosphate (HMBPP) or clinically approved aminobisphosphonates have been described. These approaches have seemingly safely treated over 250 cancer patients, although complete remissions are extremely rare. However, there remains a need for activating agents with a proven ability to expand large numbers of γδ T cells.

[0009] Furthermore, binders or activators that can preferentially target, bind to, recognize, specifically modulate, or increase the number of V51+ cells in situ in vivo may be highly desirable as pharmaceutical agents.

[0010] However, although drugs exist that may modulate V52+ cells, including aminobisphosphonates such as Zometa® (zoledronic acid), these medications are primarily designed to slow bone resorption. Despite this modulation of V52+, there is a need to develop medications specifically designed to bind, target, modulate, activate, or increase the number of V51+ cells, for example, because repeated modulation of V52+ may result in a persistent and progressive exhaustion phenotype.

[0011] Furthermore, given that V51+ cells are primarily tissue-resident, an ideal drug capable of modulating V51+ would also exhibit fewer undesirable "off-target" effects and rapid renal clearance. Typically, these undesirable effects can manifest when using small molecule chemicals. For example, the aforementioned aminobisphosphonates, which have been shown to modulate a distinct class of V52+ cells (secondary to their primary regulatory effect on bone), are associated with nephrotoxicity, manifested as worsening renal function and potentially renal failure (e.g., Markowitz et al. (2003) Kidney Int. 64(1):281-289). Additional undesirable effects of Zometa listed by the European Medicines Agency include anemia, hypersensitivity reactions, hypertension, atrial fibrillation, muscle pain, general pain, fatigue, increased blood urea, vomiting, joint swelling, and chest pain.

[0012] The in situ environment in which vδ1+ cells are found must also be considered. For example, it has previously been shown that nonhematopoietic tissue-resident γδ T cells exhibited robust proliferative responses when initially isolated from tissue, but only in the absence of direct cell-cell contact with autologous fibroblasts. It has been discovered that nonhematopoietic tissue-resident T cells (γδ T cells) must be separated from nonhematopoietic cells (e.g., stromal cells, particularly fibroblasts) to function. This is because direct contact of lymphocytes with stromal or epithelial cells appears to inhibit the proliferation of tissue-resident γδ T cells. The observation that pre-activated cells exist in a more suppressed state in situ is another reason why vδ1+ cells have not previously been considered a promising therapeutic target. Indeed, until the discoveries described herein, no method had been devised that could effectively and selectively modulate blood and tissue vδ1+ cells in situ, when these cells are typically considered to be in a "resting," "pre-activated," or "non-activated" state.

[0013] Thus, there is a need for improved drugs that are specifically designed to target V51+ cells and treat infectious diseases, autoimmune conditions, and cancer. Specifically, there is a need for drugs that can be administered to ameliorate the signs and symptoms of disease by specifically binding to, targeting, activating, enhancing the proliferation and / or cytotoxic activity of, or blocking the activation of V51+ cells.

[0014] Bispecific and multispecific antibodies in various formats have been developed for various therapeutic applications. Bispecific and multispecific antibodies can be classified into overlapping yet distinct classes based on the type of biological target and mode of action. For example, such multispecific antibodies can be classified into classes such as cytotoxic effector cell redirectors (also known as bispecific T cell engaging antibodies, bispecific T cell engagers, TCEs, or BiTEs) and dual immunomodulators (DIs).

[0015] T-cell engagers (TCEs) are designed to enhance a patient's immune response against tumors by targeting T cells to tumor cells or vice versa. They function by targeting a first epitope (usually CD3) on the T-cell receptor complex of a T cell and a second epitope that is a cancer antigen or a cancer-associated antigen (TAA), such as a cancer antigen or tumor-associated antigen (TAA). Such antibodies colocalize with tumor cells and T cells to promote tumor cell killing. Examples of BiTEs include the CD3 x CD19 bispecific antibody blinatumomab, the CD3 x EpCAM bispecific antibody catumaxomab, and the CD3 x HER2 bispecific antibody ertumaxomab. TCEs, such as BiTEs, are typically provided in scFv format, although other formats are also available. For example, BiKE is similar to BiTEs but targets CD16 on NK cells instead of CD3.

[0016] The T cell receptor (TCR) has been described as the most complex receptor structure in the mammalian immune system. It constitutes a transmembrane multiprotein receptor complex containing the T cell receptor in close proximity to several CD3 chains. For example, in mammals, a typical such complex contains the T cell receptor, CD3γ chain, CD3δ chain, and two CD3ε chains. These chains associate with the T cell receptor (TCR) alongside the associated ζ chain (zeta chain), which then generates the typical activation signal in T lymphocytes. However, alternative complexes have also been reported. For example, a T cell receptor complex containing the T cell receptor and a ζ chain homodimer has been described. Additional coreceptors, such as CD4 and CD8, can also support TCR function.

[0017] Regardless of the composition of the receptor complex, it is well established that the complex translates cell surface binding events into intracellular phosphorylation signaling cascades that ultimately result in the activation of transcription factors such as NFAT and NFkB, which lead to increased expression of cytokines and effector proteins such as granzymes and perforin.

[0018] However, although using such TCEs to treat cancer remains a compelling concept, to date, even after 30 years of concerted efforts to advance TCEs in early clinical development, many such bispecific antibodies have demonstrated poor safety, efficacy, and manufacturability profiles. In fact, as of January 2020, the only TCE that has not been withdrawn after approval remains blinatumomab. This TCE multispecific antibody fragment binds to the T cell receptor complex with one binding arm and to the CD19 target with the second binding arm.

[0019] Bispecific T cell-engaging antibodies have been described in Lejeune et al., 2020, Front Immunol., 11:762. However, existing bispecific antibodies in this category, particularly those that engage T cells through CD3 binding, have significant off-target effects that result in severe adverse effects, given the potency of the CD3 antigen as a signaling molecule and its ubiquitous presence in patient T cell populations. Thus, for example, in the case of CD3-targeting bispecifics such as catumaxomab (now withdrawn), systemic delivery (e.g., intravenous) is practically impossible. Instead, more limited delivery, such as intraoperative, intraperitoneal, or intraperitoneal delivery, is more frequently intended. This limits the selectivity and use of these bispecifics as drugs. In fact, even anti-CD3 antibodies with attenuated effector function (i.e., T cell complex engagers that target CD3 but are not bispecific) present challenges for intravenous delivery due to associated toxicities. For example, the anti-CD3 antibody foralarumab is currently mostly intended for oral delivery (eg, in the treatment of gastrointestinal diseases) to limit exposure and reduce toxicity.

[0020] Many of the current problems observed with such TCEs in early clinical trials are often attributed to the high-affinity T cell complex binding domains used. It has been proposed that this is because the designers of these TCEs did not fully consider the low affinity of the natural TCR complex binding event, resulting in severe dose-limiting toxicities and a very narrow therapeutic window. In this regard, it has been emphasized that many early TCE drug developers relied on three anti-CD3 T cell complex binding domains derived from OKT3, SP34, and UCHT1. All of these original binding domains bind with relatively high affinities in the single- to low-double-digit nM range, equivalent to approximately 1,000-fold higher affinities than the natural binding event. As a result, it has been proposed that T cell activation is significantly different (and often unfavorable) compared to the natural T cell receptor complex binding event. For example, TCE developers using platforms based on the higher affinity OKT3 may be swayed by the fact that OKT3 induces T cell apoptosis in the presence of IL-2.

[0021] For these reasons, lower affinity T cell complex binding has emerged as an important consideration for determining the design parameters of T cell-engaging bispecific antibody therapeutics.

[0022] Another issue in designing TCEs is the need to attenuate Fc function. Indeed, because Fc binding to Fcγ receptors (FcγRs) triggers immune effector cell activation, TCEs typically require complete suppression of Fc-mediated effector functions to maximize therapeutic efficacy and minimize off-target toxicity. In fact, the majority of CD3-targeting bispecific antibodies currently used in clinical practice have Fc domains with reduced FcγR binding activity or are bispecific fragments that intentionally lack an Fc region. In general, TCEs with unattenuated Fc function are expected to induce antibody-dependent cellular cytotoxicity (ADCC), thereby depleting the γδ T cell population recognized by the antibody. However, again, attenuating such functions to avoid toxicity / safety complications, e.g., by engaging CD16+ or CD32+ or CD64+ immune cells, or by reducing the half-life of the bispecific (e.g., when using smaller bispecific antibody fragments such as BITE), may also attenuate potentially important efficacy aspects. Methods that reduce the interaction of FcγR and TCE (e.g., using IgG formats designed to reduce such interactions) are expected to reduce Fc-mediated TCE immobilization and reduce TCR clustering due to cross-linking with immobilized TCE.

[0023] To address some, but not all, of these issues, numerous companies, including Xencor (Pasadena, CA), Macrogenics (Gaithersburg, MD), and Genentech (San Francisco, CA), have recently reported reducing the binding affinity of the T cell receptor complex-binding arm of their respective TCE platforms. However, reducing the binding affinity can result in reduced efficacy and reduced selectivity with respect to the design and functionality of TCEs. For example, it has now been demonstrated that the affinity of the binding domain in such TCEs determines their distribution profile in vivo. Specifically, it is typically observed that the distribution of TCEs is biased toward targets for which they have the highest affinity. Thus, reducing the affinity of the TCE binding domain for the T cell complex typically biases distribution away from T cells, the very cells required for the efficacy of such TCEs. It is for this reason, in part, that TCEs are said to have an "extremely narrow" therapeutic window.

[0024] Furthermore, significant hurdles remain for immunomodulatory therapeutics, particularly in solid tumors. For example, current state-of-the-art approaches include CD3-targeting bispecific drugs, where one domain binds to CD3 and the second domain targets a TAA. However, these have proven problematic in many cases. For example, Middelburg J, et al. Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors. Cancers. 2021;13(2):287 summarizes some of these hurdles for multispecific immunomodulatory moieties that engage with T cells in the solid tumor space, including: i. On-target and off-tumor toxicity issues: For example, the authors emphasize that TAAs in solid tumors are often also expressed in healthy organ tissues, which can result in organ dysfunction that can lead to immunopathology and death, as shown in mouse preclinical studies using CD3 bispecific drugs. ii. Availability of effector cells in the tumor microenvironment (TME): For example, conventional CD3+ "naive" T cells reside primarily in the blood and lymphatic systems without further activation by dendritic cells. iii. Quality of tumor infiltrating lymphocytes (TILs), considering that TILs may contain CD3+ Treg cells and / or exhausted CD3+ cells: For example, bispecific drugs targeting CD3 may induce TIL apoptosis by activation-induced cell death, which prevents a potent anti-tumor response.

[0025] Thus, there is a need for improved multispecific immunomodulatory drugs in which at least one binding domain binds to a T cell and at least one second binding domain targets a TAA.

[0026] There is also a need for improved drugs that are specifically designed to target V51+ cells to treat infectious diseases, autoimmune conditions, and cancer. Specifically, there is a need for drugs that can be administered to ameliorate the signs and symptoms of disease by specifically binding to, targeting, activating, enhancing the proliferation and / or cytotoxic activity of, or blocking the activation of V51+ cells. Summary of the Invention

[0027] The present invention relates to high-affinity antibodies ("multispecific antibodies") comprising multiple antigen-binding sites, including an antigen-binding site for TCR delta variable region 1 (V51) and an antigen-binding site for EGFR. More specifically, the present invention relates to multispecific antibodies comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site specific for an epitope of the variable delta 1 (V51) chain of the gamma delta T cell receptor (TCR), and the Fc region comprises a binding site specific for EGFR.

[0028] The multispecific antibodies of the present invention are referred to as "mAbs 2The format known as "mAb" or "mAb-double antibody" is an antibody that contains an Fc region engineered to include an antigen-binding loop in the CH3 domain. This modified Fc region is called an "Fcab" (antigen-binding Fc). The resulting Fcab can be rapidly inserted into a native IgG antibody format to produce a tetravalent mAb that binds two different antigens. 2 Bispecific antibodies can be made. Thus, mAbs 2 The antibody further comprises a Fab region comprising a VH-VL domain pair that provides an antigen-binding site. 2 The molecule comprises an EGFR-binding Fcab and a vδ1-binding Fab.

[0029] The antibodies of the present invention have a favorable functional profile. In particular, unlike prior art anti-V51 antibodies that focus on depleting V51 T cells, the antibodies of the present invention are useful for activating V51 T cells. While the antibodies of the present invention can downregulate the TCR on T cells to which they bind, they do not cause V51 T cell depletion but rather stimulate T cells, making them useful in therapeutic settings that benefit from activation of this T cell compartment. Activation of V51 T cells is evident from TCR downregulation and changes in activation markers, such as CD25, Ki67, the degranulation marker CD107a, NCR (natural cytotoxicity receptor), and / or 4-1BB. Activation of V51 T cells then triggers the release of proinflammatory cytokines, such as INFγ and TNFα, promoting immune licensing. Surprisingly, antibodies with appropriately high affinity for TRDV1 induce increased V51 T cell killing, and unlike antibodies targeting (for example) CD3, high-affinity antibodies can be provided without the side effects associated with extensive CD3 activation. As a result, high-affinity antibodies can induce potent immunostimulatory effects by tumor-infiltrating lymphocytes (TILs). This can be achieved with minimal exhaustion or killing of V51 cells. Thus, the multispecific antibodies of the present invention can be considered agonistic antibodies.

[0030] The Fcab region contained in the multispecific antibodies of the present invention has a smaller binding interface than a typical monoclonal antibody binding site. When the Fab arms of a typical mAb are separated by a flexible hinge region, the Fcab binding site forms a compact antibody fragment with two closely located binding sites. The two antigen-binding sites of an Fcab are also spatially closer to each other than the antigen-binding sites of a typical mAb. Based on this smaller binding interface and the reduced flexibility of the two binding sites, it is surprising that the multispecific antibodies of the present invention (containing the Fcab region) can bind to and inhibit EGFR with affinity and potency similar to that of benchmark monoclonal antibodies.

[0031] According to a first aspect of the present invention, there is provided a multispecific antibody comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site specific for an epitope of the variable δ1 (Vδ1) chain of the γδ T cell receptor (TCR), and the Fc region comprises an EGFR-binding site.

[0032] In a second aspect, the present invention provides polynucleotide sequences encoding the multispecific antibodies of the present invention, for example, polynucleotide sequences encoding the first binding domain of anti-Vδ1, comprising a sequence having at least 70% sequence identity to SEQ ID NOs: 199-222, 224-247, 249-259, or 261-271.

[0033] In a third aspect of the present invention, there is provided an expression vector comprising a polynucleotide sequence of the present invention. Host cells comprising the polynucleotide sequence of the present invention or the expression vector of the present invention are also provided. Also provided is a method for producing any of the multispecific antibodies or antigen-binding fragments thereof of the present invention, the method comprising culturing a host cell of the present invention in a cell culture medium.

[0034] In a further aspect of the present invention, compositions comprising the multispecific antibodies of the invention are provided. Pharmaceutical compositions comprising the multispecific antibodies of the invention and a pharmaceutically acceptable diluent or carrier are also provided. The compositions and pharmaceutical compositions may optionally further comprise one or more additional therapeutically active agents.

[0035] In a further aspect of the invention, there is provided a kit comprising a multispecific antibody of the invention or a pharmaceutical composition of the invention, and optionally comprising instructions for use and / or an additional therapeutically active agent.

[0036] In a further aspect of the present invention, there is provided a method for treating a disease or disorder in a subject, the method comprising administering to the subject a multispecific antibody of the invention or a pharmaceutical composition of the invention. There is also provided a method for modulating an immune response in a subject, the method comprising administering to the subject a multispecific antibody of the invention or a pharmaceutical composition of the invention. The antibody administered to the subject may be in a therapeutically effective amount.

[0037] In a still further aspect of the invention there is provided a multispecific antibody of the invention, or a pharmaceutical composition of the invention, or a kit of the invention for use in medical treatment. There is also provided the use of a multispecific antibody of the invention in the manufacture of a medicament. [Brief explanation of the drawings]

[0038] [Figure 1A] Phage selection rounds. Phage selection rounds 1 to 3 against the ADT1-7 library. [Figure 1B] Phage selection rounds. Phage selection rounds 1 to 3 for the ADT1-4 library. [Figure 1C] Phage selection rounds. Phage selection rounds 1 to 3 of the ADT1-4 library using a selection strategy to isolate cynomolgus monkey cross-reactive binders. [Figure 2A] Schematic of selection of mature antibodies by mammalian display. Schematic of flow sorting of the ADT1-7 library. [Figure 2B]Schematic of selection of mature antibodies by mammalian display. Schematic of flow sorting of ADT1-4 library 1 (human). [Figure 2C] Schematic of selection of mature antibodies by mammalian display. Schematic of flow sorting of ADT1-4 library 2 (cynomolgus monkey). [Figure 3A] Impact of the S74L change on affinity. ADT1-4 lineage mammalian display output: human dissociation off-rate (SPR) versus human antigen binding (Delfia ELISA, 0.4 nM human antigen) shown using LC 74S (open circles) or 74L (filled circles). The results highlight the good match between affinity improvement by SPR and affinity improvement by antigen binding by Delfia ELISA. These results also highlight the improved binding conferred by the variable domain S74L modification. [Figure 3B] Effect of the S74L change on affinity. ADT1-4 lineage mammalian display output: Cynomolgus dissociation off-rate (SPR) versus Cynomolgus antigen binding (Delfia ELISA, 10 nM Cynomolgus antigen) shown using LC 74S (open circles) or 74L (filled circles). [Figure 3C] Effect of the S74L change on affinity. ADT1-4 lineage mammalian display output: Correlation between improvement in human antigen dissociation off-rate (SPR) and cynomolgus antigen dissociation off-rate (SPR) with the addition of the indicated LC 74S (open circles) or 74L (filled circles). [Figure 4A]CDR3 Usage and Cross-Sharing. Exemplary heavy and light chain cross-sharing among affinity-matured antibodies in the ADT1-4(G04) series (heat map of ELISA results for 0.4 nM human TRDV1 graded). This "heat map" shows cross-sharing of CDR3 sequences among different affinity-matured antibodies in the ADT1-4 series, demonstrating that the affinity maturation process resulted in antibody sequences that did not necessarily present as specific heavy and light chain pairs. This result highlights that affinity-matured antibodies can cross-share light and heavy chains, and that different LC / HC combinations can yield comparable or improved results in high-stringency antigen-binding studies. The ADT1-4(G04) parent clone is also included in this figure (bottom left). [Figure 4B] CDR3 usage and cross-sharing. Final selection of the ADT1-4 lineage: CDR3 usage and cross-sharing and cynomolgus antigen binding "heat map" of the starting parent ADT1-4 relative to the parent G04 mAb (bottom left). [Figure 4C] CDR3 Usage and Cross-Sharing. Final selection of the ADT1-7 lineage: CDR3 usage and cross-sharing and human antigen binding "heat map" relative to the starting ADT1-7 parental E07 mAb (bottom left). [Figure 5] Fold enhancement in binding of the ADT1-4 lineage compared to the ADT1-4 parent G04. (A) Fold enhancement of recombinant human Vδ1 antigen binding. (B) Fold enhancement of recombinant cynomolgus monkey Vδ1 antigen binding. (C) Fold enhancement of primary Vδ1 MFI. (D) Fold enhancement of PEER Vδ1 cell line MFI. [Figure 6] Fold enhancement in binding of the ADT1-1 line compared to the ADT1-4 parent E07. (A) Fold enhancement of recombinant human Vδ1 antigen binding. (B) Fold enhancement of primary Vδ1 MFI. (C) Fold enhancement of PEER Vδ1 cell line MFI. [Figure 7A] Fold improvement in binding to human (and cynomolgus) antigen compared to the parental clone. Fold improvement in binding to human antigen. DELFIA ELISA signal of affinity matured clones versus parental ADT1-4 (G04), 0.4 nM recombinant human L1 antigen (containing human Vδ1 TCR antigen). [Figure 7B] Fold improvement in binding to human (and cynomolgus) antigen compared to parental clone. Fold improvement in binding to cynomolgus antigen (DV1 / GV77 containing cynomolgus SEQ ID NO: 308 (mature, minus leader)). DELFIA ELISA signal of affinity matured clones vs. parental ADT1-4 (G04), recombinant human L1 antigen at 0.4 nM. [Figure 7C] Fold improvement in binding to human (and cynomolgus) antigen compared to the parental clone. Fold improvement in binding to human antigen. DELFIA ELISA signal of affinity matured clones versus parental ADT1-7 (E07), recombinant human L1 antigen at 0.4 nM. [Figure 8A] Fold improvement in KD for human (and cynomolgus monkey) antigens compared to the parental clone. Fold improvement in human antigen KD for the ADT1-4 (G04) series. [Figure 8B] Fold improvement in KD for human (and cynomolgus) antigens compared to the parental clone. Fold improvement in cynomolgus antigen KD for the ADT1-4 (G04) series. [Figure 8C] Fold improvement in KD for human (and cynomolgus) antigens compared to the parental clone. Fold improvement in human antigen KD for the ADT1-7 (E07) series. [Figure 9A] Binding affinity analysis for human Vδ1 antigen (KD by SPR). Surface plasmon resonance of the ADT1-4 series. [Figure 9B] Binding affinity analysis (KD) for human Vδ1 antigen by SPR. Surface plasmon resonance of the ADT1-7 series. [Figure 9C] Binding affinity analysis for human Vδ1 antigen (KD by SPR). KD values ​​of the ADT1-4 series and fold change compared to the parent clone. [Figure 9D] Binding affinity analysis for human Vδ1 antigen (KD by SPR). KD values ​​of the ADT1-7 series and fold change compared to the parent clone. [Figure 9E] Binding affinity analysis (KD by SPR) for human Vδ1 antigen. Fold change in KD relative to the parental clone of the ADT1-4 series. [Figure 9F]Binding affinity analysis (KD by SPR) for human Vδ1 antigen. Fold change in KD relative to the parental clone of the ADT1-7 series. [Figure 10] Binding affinity analysis for cynomolgus monkey antigen (KD by SPR). (A) Surface plasmon resonance of the ADT1-4 series against cynomolgus monkey antigen. (B) KD values ​​of the ADT1-4 series against cynomolgus monkey antigen. [Figure 11A] Binding affinity to cell surface Vδ1 TCR (EC50 of binding to cell surface Vδ1). Binding levels by Vδ1 mAbs to γδ T cell donor ATS006. [Figure 11B] Binding affinity to cell surface Vδ1 TCR (EC50 of binding to cell surface Vδ1). Binding levels by Vδ1 mAbs to γδ T cell donor TS164. [Figure 11C] Binding affinity to cell surface V51 TCR (EC50 of binding to cell surface V51). Bar graph showing the mean 50% binding values ​​from ADT1-4 and ADT1-7 clones binding to V51-positive γδ T cells expressed as the average of two donors; these values ​​are shown in the table along with the % improvement. [Figure 11D] Binding affinity to cell surface V51 TCR (EC50 of binding to cell surface V51). Table summarizing IC50 plotted in (A) and (B) and V51-negative cell types including HEK293A, Raji cells, and various leukocyte subsets including primary blood mononuclear cells. For V51-positive γδ T cells, data are presented as the average of two donors. [Figure 12A] TCR downregulation. ADT1-4 series. [Figure 12B] TCR downregulation. ADT1-7 series. [Figure 12C] TCR Down-Modulation. Mean TCR Down-Modulation-IC50 results from two GD cell donors. [Figure 12D] TCR downregulation. Fold improved TCR downregulation from the parental ADT1-4 clone. [Figure 12E]TCR downregulation. Fold improved TCR downregulation from the parental ADT1-7 clone. [Figure 12F] TCR downregulation. Median effect size from (C), and improvement rates were calculated from each parent for ADT1-4 (top) and ADT1-7 (bottom). [Figure 12G] TCR downregulation. Median effect values ​​from (C), fold improvement calculated from each parent for ADT1-4 (top) and ADT1-7 (bottom). [Figure 13A] Vδ1 monoclonal antibody against γδ activation as measured by CD107a expression. ADT1-4-2 clone in GD cells alone. [Figure 13B] Vδ1 monoclonal antibody against γδ activation as measured by CD107a expression. ADT1-4-2 clone in GD cells combined with THP-1 cells. [Figure 13C] Vδ1 monoclonal antibody against γδ activation measured by CD107a expression. ADT1-7-3 clone in GD cells alone. [Figure 13D] Vδ1 monoclonal antibody against γδ activation as measured by CD107a expression. ADT1-7-3 clone in GD cells combined with THP-1 cells. [Figure 13E] Vδ1 monoclonal antibodies on γδ activation as measured by CD107a expression. Table showing the percent increase in γδ CD107a expression from co-cultured cells treated with the highest concentration of Vδ1 mAb compared to untreated, non-co-cultured γδ cells. [Figure 13F] V51 monoclonal antibody on γδ activation measured by CD107a expression. Table showing the percent increase in γδ CD107a expression from co-cultured cells treated with the highest concentration of V51 mAb compared to untreated, co-cultured and non-co-cultured γδ cells. [Figure 14A] Vδ1 monoclonal antibody against γδ activation measured by CD25 expression. ADT1-4-2 clone on GD cells alone. [Figure 14B]Vδ1 monoclonal antibody against γδ activation as measured by CD25 expression. ADT1-4-2 clone in GD cells combined with THP-1 cells. [Figure 14C] Vδ1 monoclonal antibody against γδ activation measured by CD25 expression. ADT1-7-3 clone on GD cells alone. [Figure 14D] Vδ1 monoclonal antibody against γδ activation as measured by CD25 expression. ADT1-7-3 clone in GD cells combined with THP-1 cells. [Figure 14E] Vδ1 monoclonal antibodies on γδ activation as measured by CD25 expression. Table showing the percent increase in γδ CD25 expression from co-cultured cells treated with the highest concentration of Vδ1 mAb compared to untreated, non-co-cultured γδ cells. [Figure 14F] V51 monoclonal antibodies on γδ activation as measured by CD25 expression. Table showing the percent increase in γδ CD25 expression from co-cultured cells treated with the highest concentration of V51 mAb compared to untreated, co-cultured and non-co-cultured γδ cells. [Figure 15] Cynomolgus monkey TCR down-regulation. (A) Comparison of the ability of ADT1-4-2 and ADT1-4 to engage and reduce VD1 expression on cynomolgus monkey γδ-T cells. (B) Percentage of cell surface expression of VD1 upon treatment with ADT1-4-2. (C) Individual EC50 values ​​from different donors combined with mean and standard deviation. [Figure 16A] Quantification of viable THP-1 cell numbers after 24 h of co-culture with γδ T cells in the presence of Vδ1 mAb or control. THP-1 cell killing assay of ADT1-4 clones. [Figure 16B] Quantification of viable THP-1 cell numbers after 24 h of co-culture with γδ T cells in the presence of Vδ1 mAb or control. THP-1 cell killing assay of ADT1-7 clone. [Figure 16C]Quantification of viable THP-1 cell numbers after 24 h of co-culture with γδ T cells in the presence of Vδ1 mAb or control. Mean EC50 in the THP-1 killing assay of ADT1-4 and ADT1-7 clones. [Figure 16D] Quantification of viable THP-1 cell numbers after 24 h of co-culture with γδ T cells in the presence of Vδ1 mAb or control. Table summarizing EC50s plotted in (C). [Figure 17] Vδ1 monoclonal antibody for antibody-dependent cellular cytotoxicity (ADCC). [Figure 18] Vδ1 monoclonal antibody against complement-dependent cytotoxicity (CDC). [Figure 19] Sparing of healthy cells by clone ADT1-4-2. [Figure 20A] Effect of anti-V51 antibodies on TIL populations from primary tumor biopsies. Percent reduction in V51 TCR expression on total tumor-infiltrating γδ T cells after 48 hours of mAb stimulation in two separate donors is shown, confirming target engagement in each case. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20B] Effect of anti-V51 antibodies on TIL populations from primary tumor biopsies. Percent reduction in V51 TCR expression on total tumor-infiltrating γδ T cells after 72 hours of mAb stimulation in two separate donors is shown, confirming target engagement in each case. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20C]Effect of anti-V51 antibodies on TIL populations from primary tumor biopsies. Figure 1 shows enhanced expression of both CD25 and Ki67 on V51+ T cells after 48 hours of stimulation with ADT1-4-2 compared to stimulation with the IgG1 isotype control or ADT1-4. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20D] Effect of anti-Vδ1 antibodies on TIL populations from primary tumor biopsies. Figure 1 shows the substantial fold increase in IFN-γ production by TILs stimulated with ADT1-4-2 or ADT1-7-3 for 72 hours in the presence of 50 ng / ml IL-15. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20E] Effect of anti-Vδ1 antibodies on TIL populations from primary tumor biopsies. Stimulation of TILs with ADT-1-4-2 or ADT1-7-3 did not enhance secretion of the type 17-associated cytokines IL-6 or IL-17 at this time point. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20F] Effect of anti-V51 antibodies on TIL populations from primary tumor biopsies. Percent reduction in V51 TCR expression in total tumor-infiltrating γδ T cells 24 hours after mAb stimulation in two separate donors is shown, confirming target engagement in TILs isolated by enzymatic digestion. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20G]Effect of anti-V51 antibodies on TIL populations from primary tumor biopsies. Percent reduction in V51 TCR expression in total tumor-infiltrating γδ T cells 72 hours after mAb stimulation in two separate donors is shown, confirming target engagement in TILs isolated by enzymatic digestion. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20H] Effect of anti-Vδ1 antibodies on TIL populations from primary tumor biopsies. Showing dose-dependent enhancement of Ki67 expression on γδ T cells after 72 hours of stimulation with ADT1-4-2. In all cases, the concentrations of control anti-RSV and parental ADT1-4 match the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20I] Effect of anti-Vδ1 antibodies on TIL populations from primary tumor biopsies. The fold increase in IFN-γ produced by TILs isolated from two individual donors by enzymatic digestion and stimulated with ADT1-4-2 at a concentration of 6.66 nM in the presence of 2 ng / ml IL-15 at 24 hours is shown. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 20J] Effect of anti-Vδ1 antibodies on TIL populations from primary tumor biopsies. The fold increase in IFN-γ produced by TILs isolated by enzymatic digestion from two individual donors and stimulated with ADT1-4-2 at a concentration of 6.66 nM in the presence of 2 ng / ml IL-15 at 72 hours is shown. In all cases, the concentrations of control anti-RSV and parental ADT1-4 matched the highest concentrations used in the study (i.e., 6.66 nM for A, C, F, G, H, I, J, and 66.6 nM for B and E). [Figure 21]Effect of anti-Vδ1 antibodies on TIL populations from primary tumor biopsies. (A) Enhanced expression of CD25 and Ki67 in γδ T cells stimulated with ADT1-4-2 for 10 days. (B) Substantial increase in perforin+ granzyme B+ γδ T cells after 10 days of stimulation with ADT1-4-2. (C) Significantly enhanced expression of granzyme B and perforin by both CD8+ and CD8- αβ T cells after 10 days of stimulation of tumor-infiltrating Vδ1+ T cells with ADT1-4-2. (D) Significantly increased production of IFN-γ and moderately increased production of IL-17 and IL-6 by lung tumor-derived TILs after stimulation with ADT1-4-2. (I) Enhanced production of the chemokines CCL2, CCL4, and CXCL10 by TILs after 10 days of stimulation with ADT1-4-2. In all cases, the control anti-RSV and parental ADT1-4 matched the same concentrations as affinity matured ADT1-4-2. [Figure 22] Sequence of ADT1-4 series clone (light chain). [Figure 23] Sequence of ADT1-4 series clone (heavy chain). [Figure 24] Sequence of ADT1-7 series clone (light chain). [Figure 25] Sequence of ADT1-7 series clone (heavy chain). [Figure 26A] The V51 / EGFR bispecific antibodies exhibit high affinity binding to human EGFR and human V51 binding affinity comparable to their parental mAbs. Surface plasmon resonance (SPR) analysis was performed with the V51 / EGFR bispecific variants to assess binding to human V51. For comparison purposes, the parental mAb, cetuximab, and a negative control mAb were included. [Figure 26B] The V51 / EGFR bispecific antibodies exhibit high affinity binding to human EGFR and human V51 binding affinity comparable to their parental mAbs. Surface plasmon resonance (SPR) analysis was performed with the V51 / EGFR bispecific variants to assess binding to the human EGFR antigen. For comparison purposes, the parental mAb, cetuximab, and a negative control mAb were included. [Figure 27A]Vδ1 / EGFR bispecific antibodies bind to EGFR+ A431 target cells and Vδ1γδ T cells. Cell surface expression of EGFR and Vδ1 on the A431 cell line and primary Vδ1γδ T cells. Target cells were stained with various concentrations of antibody followed by a fluorescent anti-human IgG detection antibody. All incubation steps were performed at 4°C, and mAb binding was determined by measuring median fluorescence levels using flow cytometry. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. [Figure 27B] V51 / EGFR bispecific antibodies bind to EGFR+ A431 target cells and V51γδ T cells. Levels of binding by V51 / EGFR bispecific antibodies to the A431 cell line or primary V51γδ T cells. Target cells were stained with various concentrations of antibody followed by staining with a fluorescent anti-human IgG detection antibody. All incubation steps were performed at 4°C, and mAb binding was determined by measuring median fluorescence levels using flow cytometry. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. [Figure 28A] The Vδ1 / EGFR bispecific antibody induces activation and degranulation of EGFR-specific T cells, resulting in increased γδ T cell-mediated cytotoxicity of A431 target cells. Cell surface expression of the γδ TCR on primary Vδ1 γδ T cells after 24 hours of culture with the bispecific antibody in the presence or absence of A431 cells. In all cases, fluorescence was determined using flow cytometry to measure median fluorescence levels. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. Data are presented as the mean ± SD of two biological replicates. [Figure 28B]Vδ1 / EGFR bispecific antibodies induce activation and degranulation of EGFR-specific T cells, resulting in increased γδ T cell-mediated cytotoxicity of A431 target cells. The number of viable A431 cells after 24 hours of co-culture at a 1:1 ratio with various antibody concentrations. Viability was measured using a viability dye, and activation status was measured using a CD25 antibody. In all cases, fluorescence was determined using flow cytometry to measure median fluorescence levels. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. Data are presented as the mean ± SD of two biological replicates. [Figure 28C] Vδ1 / EGFR bispecific antibodies induce activation and degranulation of EGFR-specific T cells, resulting in increased γδ T cell-mediated cytotoxicity of A431 target cells. Activation status of primary Vδ1 γδ T cells after 24 hours of co-culture at a 1:1 ratio with various antibody concentrations. Viability was measured using a viability dye, and activation status was measured using a CD25 antibody. In all cases, fluorescence was determined using flow cytometry to measure median fluorescence levels. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. Data are presented as the mean ± SD of two biological replicates. [Figure 28D] Vδ1 / EGFR bispecific antibodies induce activation and degranulation of EGFR-specific T cells, resulting in increased γδ T cell-mediated cytotoxicity of A431 target cells. Degranulation of primary Vδ1 γδ T cells after 4 hours of co-culture with A431 cells at a 1:1 ratio in conjunction with various antibody concentrations. Degranulation was determined by adding a fluorophore-conjugated anti-CD107α antibody directly to the cell-antibody mix at the start of the co-culture. In all cases, fluorescence was determined using flow cytometry to measure median fluorescence levels. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. Data are presented as the mean ± SD of two biological replicates. [Figure 28E]Vδ1 / EGFR bispecific antibodies induce activation and degranulation of EGFR-specific T cells, resulting in increased γδ T cell-mediated cytotoxicity of A431 target cells. Number of viable A431 cells after 24 h of coculture with 10 pM antibody and various amounts of primary Vδ1 γδ T cells. In all cases, fluorescence was determined using flow cytometry to measure median fluorescence levels. Logarithmic 4-parameter dose-response curve fitting was performed using GraphPad Prism 9. Data are presented as the mean ± SD of two biological replicates. [Figure 29] Further evidence of non-depletion and CD3 downregulation in both blood-derived and tumor-associated V51 T cells. (A) MFI of v51 TCR upon antibody stimulation as a measure of mAb target engagement in blood-derived V51 T cells. (B) MFI of CD3 expression on positively gated blood-derived v51 cells. Stimulation with v51 antibodies engaged v51 cells and resulted in downregulation of both v51 and CD3 on v51 cells. [Figure 30] The ADCC reporter bioassay does not demonstrate ADCC as a result of anti-vδ1 antibodies. Target cells, i.e., γδ cells, were incubated with ADCC bioassay effector cells in the presence of anti-vδ1 antibodies, anti-vδ1 LAGA antibodies (Fc-disabled), and RSV isotype control. Luminescence signals were recorded as relative light units (RLU), and fold induction was calculated as described in the methods. N = 2 γδ donors (performed in technical duplicates) for "anti-vδ1 antibodies," "anti-vδ1 LAGA antibodies," "RSV," and "OKT3." N = 1 Raji cell line for the "rituximab + Raji" condition (technical duplicate). N = 1 γδ donor for the "anti-vδ1 antibodies + effector" and "anti-vδ1 LAGA antibodies + effector" conditions (performed in technical duplicate and singlet, respectively). The effector:target ratio was 3:1. [Figure 31]Multispecific antibodies conferred enhanced V51+ effector cell-mediated cytotoxicity. Targeting tissue-centric disease-associated antigens: (A-D) Example of co-culture of V51+ effector cells with A-431 cancer cells with or without (+ / -) a multispecific antibody containing an anti-V51 x anti-TAA(EGFR) bispecific binding site in which the anti-V51 VL+VH binding domain (for the first target) is paired with the CH1-CH2-CH3 domains of an anti-EGFR binding site (for the second target). (E-H) Example of co-culture of V51+ effector cells with A-431 cancer cells with or without a multispecific antibody containing an anti-V51 x anti-TAA(EGFR) bispecific binding site, in which the anti-V51 binding domain (against the first target) comprises a full-length antibody (VH-CH1-CH2-CH3 / VL-CL) and is then combined with an anti-EGFR cetuximab-derived scFv binding site (against the second target). [Figure 32] Sequence alignment and sequence of the EGFR binding domain (IgG1 CH1-CH2-CH3) showing changes relative to IgG1 CH3 (EU numbering). [Figure 33] Table showing cross-referenced CH3 residue numbering. This table is adapted from IMGT.org. Modified amino acid positions according to IMGT (standard), IMGT (exonic), EU, and Kabat numbering referenced elsewhere herein are highlighted by shading. Note that the necessary but unconventional position nomenclature to describe the additional amino acid insertion found in the example EGFR binding construct is also shown. See below: positions 21.1 (IMGT exonic column) / 361.1 (EU column) / 384.1 (Kabat column) / 17.1 (IMGT standard column). [Figure 34A] Manufacturability / stability assessment of Vδ1 x EGFR multispecific antibodies: Expression and analytical studies on six molecules. Yields in CHO. [Figure 34B] Manufacturability / stability assessment of Vδ1 x EGFR multispecific antibodies: Expression and analytical studies on six molecules. Stability under accelerated storage conditions. [Figure 34C]Manufacturability / stability assessment of Vδ1xEGFR multispecific antibodies: Expression and analytical studies on six molecules. Aggregation tendency. [Figure 34D] Manufacturability / stability assessment of Vδ1 x EGFR multispecific antibodies: Expression and analytical studies on six molecules. Decay profiles under accelerated conditions (non-reduced analysis). [Figure 34E] Manufacturability / stability assessment of Vδ1 x EGFR multispecific antibodies: Expression and analytical studies on six molecules. Decay profiles under accelerated conditions (reduction analysis). [Figure 34F] Manufacturability / stability assessment of Vδ1 x EGFR multispecific antibodies: Expression and analytical studies on six molecules. Overall summary / conclusions. [Figure 35A] Extended study of VD1xEGFR multispecific antibodies and the differential effects conferred by dialing up / down affinity in the VD1 binding arm. Affinity summary. [Figure 35B] Extended study of the differential effects conferred by dialing up / down affinity in VD1xEGFR multispecific antibodies and the VD1 binding arm. Impact on multispecific binding to tissue-resident Vδ1+ cells. [Figure 35C] Extended study of the differential effects conferred by dialing up / down affinity in VD1xEGFR multispecific antibodies and the VD1 binding arm. Impact on multispecific binding to tissue-resident Vδ1+ cells. [Figure 35D] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the VD1 binding arm. Impact on Vδ1 TCR internalization of tissue-resident Vδ1+ cells. [Figure 35E] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the VD1 binding arm. Impact on Vδ1 TCR internalization of tissue-resident Vδ1+ cells. [Figure 35F]Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the VD1 binding arm. Impact on degranulation of tissue-resident Vδ1+ cells. [Figure 35G] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the VD1 binding arm. Impact on degranulation of tissue-resident Vδ1+ cells. [Figure 35H] Extended study of VD1xEGFR multispecific antibodies and the differential effects conferred by dialing up / down affinity in the VD1 binding arm. Impact on multispecific cytolytic function against EGFR+ cancer cells. [Figure 35I] Extended study of VD1xEGFR multispecific antibodies and the differential effects conferred by dialing up / down affinity in the VD1 binding arm. Impact on multispecific cytolytic function against EGFR+ cancer cells. [Figure 35J] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the VD1 binding arm. Impact on proliferation of tissue-resident Vδ1+ cells. [Figure 35K] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the VD1 binding arm. Impact on proliferation of tissue-resident Vδ1+ cells. [Figure 35L] An extended study of VD1xEGFR multispecific antibodies and the differential effects conferred by dialing up / down affinity in the VD1 binding arm. Overall summary of this study. [Figure 35M] Extended study of VD1xEGFR multispecific antibodies and the differential effects conferred by dialing up / down affinity in the VD1 binding arm. Effect of TAA copy number. [Figure 36A]Extended study of VD1xEGFR multispecific antibodies and the differential effects conferred by dialing up / down affinity in the EGFR binding arms. Affinity summary. [Figure 36B] An extended study of the differential effects conferred by dialing up / down the affinity of the VD1xEGFR multispecific antibody and the EGFR binding arm. Effect on multispecific binding to the EGFR+ colon cancer cell line HT-29. [Figure 36C] An extended study of the differential effects conferred by dialing up / down the affinity of the VD1xEGFR multispecific antibody and the EGFR binding arm. Effect on multispecific binding to the EGFR+ colon cancer cell line HT-29. [Figure 36D] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the EGFR-binding arm. Impact on Vδ1 TCR down-regulation of tissue-resident Vδ1+ cells. [Figure 36E] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and the EGFR-binding arm. Impact on Vδ1 TCR down-regulation of tissue-resident Vδ1+ cells. [Figure 36F] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and EGFR-binding arm. Impact on degranulation of tissue-resident Vδ1+ cells. [Figure 36G] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and EGFR-binding arm. Impact on degranulation of tissue-resident Vδ1+ cells. [Figure 36H] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and EGFR-binding arm. Impact on 41BB activation status of tissue-resident Vδ1+ cells. [Figure 36I]Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and EGFR-binding arm. Impact on 41BB activation status of tissue-resident Vδ1+ cells. [Figure 36J] Extended study of the differential effects conferred by dialing up / down the affinity of the VD1xEGFR multispecific antibody and the EGFR-binding arm. Impact on multispecific cytolytic function against EGFR+ cancer cells. [Figure 36K] Extended study of the differential effects conferred by dialing up / down the affinity of the VD1xEGFR multispecific antibody and the EGFR-binding arm. Impact on multispecific cytolytic function against EGFR+ cancer cells. [Figure 36L] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and EGFR-binding arm. Impact on proliferation of tissue-resident Vδ1+ cells. [Figure 36M] Extended study of the differential effects conferred by dialing up / down affinity in the VD1xEGFR multispecific antibody and EGFR-binding arm. Impact on proliferation of tissue-resident Vδ1+ cells. [Figure 36N] An extended study of the differential effects conferred by dialing up / down the affinity of the VD1xEGFR multispecific antibody and EGFR-binding arm. The influence of affinity for EGFR and cancer cell TAA copy number. [Figure 37] Effect of affinity on preferential binding to V51 relative to EGFR cells. Effect of affinity on preferential binding to V51 relative to EGFR cells as bar graph (A), table (B) and ratio (C). [Figure 38] Effect of affinity for EGFR on internalization of multispecific antibodies by A431 tumor cells. (A)(B) Affinity for EGFR; effect on internalization of multispecific antibodies by A431 tumor cells. (C)(D) Effect on multispecific clearance by A431 tumor cells. [Figure 39] Effect of EGFR affinity on EGF ligand binding and inhibition of tumor cell proliferation by multispecific antibodies. (A)(B) Effect of EGFR affinity on EGF ligand binding and inhibition of tumor cell proliferation by multispecific antibodies. (C)(D) Effect of EGFR affinity on inhibition of EGFR+ tumor cell proliferation by multispecific agents. [Figure 40] VD1xEGFR multispecific antibody: Sparing of healthy EGFR+ cells. (A)(C) Dose-escalation effect is shown. (B) Representative microscopic images from the experiment described in (A). [Figure 41] Comparison of VD1xEGFR multispecific antibody: ADT1-4-2xFS1-67 with the lower affinity "parent" ADT1-4xFS1-67 (also known as G04 FS1-67). (A) TCR down-regulation. Dose-response comparison between ADT1-4-2xFS1-67 and ADT1-4xFS1-67. (B) Comparison of TCR down-regulation - summary of results. [Figure 42A] VD1xEGFR multispecific antibody: Comparison with CD3xEGFR multispecific antibody. Effect of T cell target receptors on Vδ1 TCR and CD3ε downregulation. [Figure 42B] VD1xEGFR multispecific antibody: Comparison with CD3xEGFR multispecific antibody. Effect of T cell target receptors on Vδ1 TCR and CD3ε downregulation. [Figure 42C] VD1xEGFR multispecific antibody: Comparison with CD3xEGFR multispecific antibody. Effect of T cell target receptors on Vδ1 TCR and CD3ε downregulation. [Figure 42D] VD1xEGFR polyspecific antibody: Comparison with CD3xEGFR polyspecific antibody. Effect on polyspecific cytolytic function against EGFR+ cancer cells. [Figure 42E] VD1xEGFR polyspecific antibody: Comparison with CD3xEGFR polyspecific antibody. Effect on polyspecific cytolytic function against EGFR+ cancer cells. [Figure 42F] VD1xEGFR polyspecific antibody: Comparison with CD3xEGFR polyspecific antibody. Effects on the induction of cytokine secretion by activated T cells. [Figure 42G] VD1xEGFR polyspecific antibody: Comparison with CD3xEGFR polyspecific antibody. Effects on the induction of cytokine secretion by activated T cells. [Figure 42H] VD1xEGFR multispecific antibody: Comparison with CD3xEGFR multispecific antibody. Effect on proliferation of tissue-resident Vδ1+ cells. [Figure 42I] VD1xEGFR multispecific antibody: Comparison with CD3xEGFR multispecific antibody. Effect on proliferation of tissue-resident Vδ1+ cells. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention provides multispecific antibodies that specifically bind to the T cell receptor of γδ T cells and specifically bind to EGFR, as well as fragments and variants thereof.

[0040] More specifically, the present invention relates to high affinity antibodies that comprise multiple antigen-binding sites ("multispecific antibodies"), including an antigen-binding site for TCR delta variable region 1 (Vdelta 1) and an antigen-binding site for EGFR.

[0041] The multispecific antibodies of the present invention are mAbs 2 The mAb is a mAb with an engineered Fc region that includes an antigen-binding loop in the CH3 domain. This modified Fc region is called an "Fcab." 2 The antibody further comprises a Fab region comprising a VH-VL domain pair that provides an antigen-binding site. 2 The molecule comprises an EGFR-binding Fcab and a vδ1-binding Fab.

[0042] More specifically, the present invention relates to the provision and characterization of optimized multispecific antibodies, for example antibodies prepared by an optimized selection procedure starting from parent anti-V51 antibodies such as the parent antibodies referred to herein as G04, E07, C08, B07, C05, E04, F07, G06, G09, B09, G10, and E01. In particular, the present invention relates to optimized multispecific antibodies derived from G04 and E07.

[0043] definition Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the meanings given them below.

[0044] Gamma delta (γδ) T cells represent a small subset of T cells that express a distinct, characteristic T cell receptor (TCR) on their surface. This TCR is composed of one gamma (γ) chain and one delta (δ) chain. Each chain contains a variable (V) region, a constant (C) region, a transmembrane region, and a cytoplasmic tail. The V region contains the antigen-binding site. Two major subtypes of human γδ T cells exist: those that predominate in peripheral blood and those that predominate in nonhematopoietic tissues. The two subtypes can be defined by the type of δ and / or γ present in the cell. For example, γδ T cells that predominate in peripheral blood predominantly express the δ variable 2 chain (Vδ2). γδ T cells that predominate in nonhematopoietic tissues (i.e., are tissue-resident) predominantly express the δ variable 1 chain. Reference to "Vδ1 T cells" or "Vδ1+ T cells" refers to γδ T cells that have a Vδ1 chain, i.e., Vδ1+ cells.

[0045] Reference to "delta variable region 1" may also be referred to as V51 or Vd1, while the nucleotides encoding the TCR chain comprising this region, or the TCR protein complex comprising this region, may be referred to as "TRDV1". Any antibody or antigen-binding fragment thereof that interacts with the V51 chain of a gamma delta TCR and also interacts with EGFR is effectively an antibody or antigen-binding fragment thereof that binds V51, and may be referred to as an "anti-TCR delta variable region 1 antibody or antigen-binding fragment thereof" or "anti-V51 antibody or antigen-binding fragment thereof" or "anti-TRDV1 antibody or antigen-binding fragment thereof" or "anti-V51xEGFR antibody or antigen-binding fragment thereof".

[0046] Reference is further made herein to other δ chains, such as the "δ variable 2" chain. These may be referred to in a similar manner. For example, the δ variable 2 chain may be referred to as V52, while the nucleotides encoding the TCR chain comprising this region, or the TCR protein complex comprising this region, may be referred to as "TRDV2." In a preferred embodiment, a multispecific antibody or antigen-binding fragment thereof that interacts with the V51 chain of a γδ TCR does not interact with other δ chains, such as V52. In the present invention, the antibody is specific for TRDV1 and does not bind to TRDV2 (SEQ ID NO: 310) or other antigens present on the γδ T-cell receptor, such as TRDV3 (SEQ ID NO: 311).

[0047] Also referred to herein is a "gamma variable chain." While these may be referred to as gamma chains or Vγ, the nucleotides encoding the TCR chain comprising this region, or the TCR protein complex comprising this region, may be referred to as TRGV. For example, TRGV4 refers to the Vγ4 chain. In preferred embodiments, a multispecific antibody or antigen-binding fragment thereof that interacts with the Vδ1 chain of a γδ TCR does not interact with a gamma chain such as Vγ4 (e.g., SEQ ID NO: 309). In preferred embodiments, the antibody also does not bind to or interact with other domains found within the γδ TCR, such as TRDJ, TRDC, TRGJ, or TRGC.

[0048] The term "T cell receptor complex" refers to the complex of proteins comprising the "T cell receptor" (or "TCR") found on the surface of T cells that is responsible for the recognition of various antigens. The T cell receptor complex either comprises the α and β chains of the T cell receptor, or in the case of γδ T cells, the γ and δ chains of the T cell receptor, as well as up to six or more additional chains, e.g., CD3δ, CD3γ, CD3ε, and CD3ζ, although the exact composition of the T cell receptor complex can vary. The T cell receptor complex mediates intracellular signaling in T cells that can lead to T cell activation.

[0049] The term "antibody" encompasses any antibody protein construct comprising at least one antibody variable domain containing at least one antigen-binding site (ABS). Antibodies include, but are not limited to, immunoglobulins of the IgA, IgG, IgE, IgD, and IgM types (and their subtypes). The overall structure of immunoglobulin G (IgG) antibodies, assembled from two identical heavy (H) chains and two identical light (L) chain polypeptides, is well established and highly conserved among mammals (Padlan (1994) Mol. Immunol. 31:169-217).

[0050] A typical antibody or immunoglobulin (Ig) is a protein comprising four polypeptide chains: two heavy (H) chains and two light (L) chains. Each chain is divided into a constant region and a variable domain. The heavy (H) chain variable domain is abbreviated herein as VH, and the light (L) chain variable domain is abbreviated herein as VL. These domains, and domains related to and derived from them, may be referred to herein as immunoglobulin chain variable domains. The VH and VL domains (also referred to as VH and VL regions) may be further divided into regions termed "complementarity-determining regions" ("CDRs"), interspersed with more conserved regions termed "framework regions" ("FRs"). The framework and complementarity-determining regions have been precisely defined (Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, (1991) NIH Publication Number 91-3242). Other numbering conventions for CDR sequences exist, such as those described in Chothia et al. (1989) Nature 342:877-883 or compiled by IMGT.org. In a conventional antibody, each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. A conventional antibody tetramer, consisting of two immunoglobulin heavy chains and two immunoglobulin light chains, is formed by the immunoglobulin heavy and light chains interconnected by disulfide bonds, and the heavy chains similarly interconnected. Thus, a whole antibody contains two Fabs, each containing a VH-VL domain pair. The heavy chain constant region contains three domains, CH1, CH2, and CH3. The light chain constant region consists of one domain, CL. The heavy chain variable domain and the light chain variable domain are binding domains that interact with antigens.The constant regions of the antibodies typically mediate the binding of the antibody to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0051] "EU numbering" refers to the numbering convention used to number amino acid residues in an antibody. Each residue in an antibody is assigned a number to allow comparison of antibodies. If a variant antibody contains a residue that was not present in the wild-type antibody (e.g., an insertion mutation), a decimal number is used to indicate the insertion. For example, if a residue is inserted between residues designated as 361 and 362, the new residue is given the EU number 361.1. EU numbering is an alternative numbering scheme to other numbering schemes such as those compiled by Kabat (Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition US Department of Health and Human Services, (1991) NIH Publication Number 91-3242), Chothia (Chothia et al. (1989) Nature 342: 877-883), or IMGT.org. [EU numbering is presented with further cross-reference to Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969). (10.1073 / pnas.63.1.78)]. Figure 33 shows the correspondence between EU numbering, IMGT numbering, and Kabat numbering of CH3 domain residues. Figure 32 shows how residues of a multispecific antibody of the invention are numbered according to the EU numbering scheme.

[0052] As used herein, "Fab region" refers to a portion of an antibody (or a construct comprising said portion) comprising a VH-VL domain pair that provides an antigen-binding site (also known as a CDR-based antigen-binding site). The Fab region may further comprise a CL domain and a CH1 domain. Thus, a conventional antibody having two heavy chains and two light chains comprises two Fabs, each comprising a VH-VL domain pair.

[0053] As used herein, "Fc region" (fragment crystallizable region) refers to a portion of an antibody (or a construct comprising said portion) comprising the CH2 and CH3 domains. The Fc region is the C-terminal region of an immunoglobulin heavy chain, including wild-type sequence Fc regions and modified Fc regions. The Fc region is a dimer and therefore comprises paired heavy chain constant regions, each comprising the CH2 and CH3 domains.

[0054] As used herein, a "fragment" of an antibody (which may also be referred to as an "antibody fragment," "immunoglobulin fragment," "antigen-binding fragment," or "antigen-binding polypeptide") refers to a portion of an antibody (or a construct comprising such a portion) that specifically binds to a first target, the delta variable region 1 (Vδ1) chain of the gamma delta T cell receptor, or a second target, EGFR (e.g., a molecule in which one or more immunoglobulin chains are not full length, but which specifically binds to the target). Examples of binding fragments encompassed by the term antibody fragment include: (i) Fab fragment (a monovalent fragment consisting of the VL, VH, CL, and CH1 domains); (ii) F(ab′)2 fragment (a bivalent fragment consisting of two Fab fragments linked by a disulfide bridge at the hinge region); (iii) Fd fragment (consisting of the VH and CH1 domains); (iv) Fv fragment (consisting of the VL and VH domains of a single arm of an antibody); (v) single-chain variable fragments (scFv) (consisting of VL and VH domains linked by a synthetic linker that allows the VL and VH regions to be produced using recombinant methods as a single protein chain to form a monovalent molecule); (vi) VH (immunoglobulin chain variable domain consisting of a VH domain); (vii) VL (immunoglobulin chain variable domain consisting of a VL domain); (viii) domain antibodies (dAbs) (consisting of either a VH or VL domain); (ix) a minibody (consisting of a pair of scFv fragments linked by a CH3 domain); and (x) diabodies, which consist of a non-covalent dimer of scFv fragments consisting of the VH domain from one antibody linked to the VL domain from another antibody by a small peptide linker; (xi) Fc fragment (consisting of CH2 and CH3 domains); (xii) Fcab fragment (consisting of an Fc fragment engineered to contain an antigen-binding loop in the CH3 domain); (xiii) the antigen-binding CH3 domain of Fcab.

[0055] A "human antibody" refers to an antibody having variable and constant regions derived from human germline immunoglobulin sequences. A human subject administered such a human antibody does not mount a cross-species antibody response (e.g., referred to as a HAMA (human anti-mouse antibody) response) to primary amino acids contained within the antibody. Such human antibodies may contain amino acid residues (e.g., mutations introduced by random or site-specific mutagenesis or somatic mutation) not encoded by human germline immunoglobulin sequences, for example, in the CDRs, particularly CDR3. However, this term is not intended to encompass antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Human antibodies that are prepared, expressed, produced, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from the assembly of a recombinant human antibody library, antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes, or antibodies prepared, expressed, produced, or isolated by any other means, including splicing human immunoglobulin gene sequences into other DNA sequences, may also be referred to as "recombinant human antibodies."

[0056] The replacement of at least one amino acid residue in a framework region of a non-human immunoglobulin variable domain with the corresponding residue from a human variable domain is called "humanization." Humanization of variable domains can reduce immunogenicity in humans.

[0057] "Specificity" refers to the number of different antigens or antigenic determinants to which a particular antibody or antigen-binding fragment thereof can bind. Antibody specificity is the antibody's ability to recognize a particular antigen as a unique molecular entity and distinguish it from other antigens. An antibody that "specifically binds" to an antigen or epitope (or is "specific" for an antigen or epitope) is a term well understood in the art. A molecule is said to exhibit "specific binding" if it reacts with a particular target antigen or epitope more frequently, more rapidly, with a longer duration, and / or with a higher affinity than it reacts with other targets. An antibody "specifically binds" to a target antigen or epitope if it binds with higher affinity, higher avidity, more readily, and / or with a longer duration than it binds to other substances.

[0058] The antibodies of the present invention are multispecific antibodies. A "multispecific antibody" is an antibody that can bind to multiple different epitopes simultaneously or sequentially. Generally, these epitopes do not exist on the same antigen. Thus, a multispecific antibody has the ability to selectively bind to epitopes present on different antigens via multiple different binding domains. This is in contrast to conventional monospecific antibodies, which do not have this ability. To be precise, a "monospecific antibody" has binding specificity for only one antigen, but may have multiple binding sites for this one antigen (for example, a fully human IgG antibody has a valency of 2, while other antibodies may have a higher valency, but if the antibody recognizes only one antigen, it is still classified as a monospecific antibody). Thus, the multispecific antibody of the present invention binds to multiple different antigens simultaneously and / or sequentially.

[0059] In some embodiments of the present invention, the antibody is a bispecific antibody. A "bispecific antibody" is an antibody that can bind to two different epitopes simultaneously and / or sequentially. Generally, these epitopes do not occur on the same antigen. Thus, a bispecific antibody has the ability to selectively bind to two different epitopes present on two different antigens via two different binding domains. This is in contrast to conventional monospecific antibodies, which do not have this ability. Thus, the bispecific antibodies of the present invention bind to two different antigens simultaneously and / or sequentially.

[0060] As used herein, "mAb" 2 "Bispecific antibody" or "mAb bispecific antibody" refers to a bispecific antibody format whereby the bispecific antibody contains an Fc region that has been engineered to contain an antigen-binding loop in its CH3 domain. This modified Fc region is called an "Fcab." mAb 2 The antibody further comprises a Fab region comprising a VH-VL domain pair which provides the antigen-binding site.

[0061] The CH3 domain of human IgG1 begins at residue 341 and ends at residue 447 (EU numbering). Residue 447 (EU numbering) may be cleaved during manufacturing and therefore may not necessarily appear in the final molecule. The CH3 domain of human IgG1 (SEQ ID NO: 563) is composed of two β-sheets formed by three and four β-strands, respectively. Three structural loops connect these β-strands at the C-terminus of the CH3 domain. In the antibodies of the present invention, these loops are engineered to form an EGFR-binding site. Residues 355-362 are defined as the "AB loop," which is the loop connecting strands A and B of the CH3 domain; residues 383-391 are defined as the "CD loop," which is the loop connecting strands C and D of the CH3 domain; and residues 413-422 are defined as the "EF loop," which is the loop connecting strands E and F of the CH3 domain. EU numbering is used (see Figure 32).

[0062] "Affinity," expressed by the equilibrium constant (KD) for the dissociation of an antigen and an antigen-binding polypeptide, is a measure of the binding strength between an antigenic determinant and an antigen-binding site on an antibody (or its antigen-binding fragment). The smaller the KD value, the stronger the binding strength between an antigenic determinant and an antigen-binding polypeptide. Alternatively, affinity can be expressed as an affinity constant (KA), which is 1 / KD. Affinity can be determined by known methods depending on the specific antigen of interest. For example, KD can be determined by surface plasmon resonance.

[0063] 10 -6 Any KD value less than 0.05 is considered to indicate binding. Specific binding of an antibody or antigen-binding fragment thereof to an antigen or antigenic determinant can be measured by any suitable known method, including, for example, Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIAs), enzyme immunoassays (EIAs), and sandwich competition assays, equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, or spectroscopy (e.g., using fluorescence assays), and various modifications thereof known in the art.

[0064] "Avidity" is a measure of the strength of binding between an antibody or antigen-binding fragment thereof and an antigen of interest. Avidity is related to both the affinity between an antigenic determinant and its antigen-binding site on the antibody and the number of pertinent binding sites present on the antibody.

[0065] "In situ" means in its native or original location, rather than transferred to another location. For example, V51 cells in situ in a patient refer to in vivo v51 cells, as opposed to cells in vitro or ex vivo.

[0066] "Human tissue V51+ cells," as well as "hematopoietic and blood V51+ cells" and "tumor-infiltrating lymphocyte (TIL) V51+ cells" are defined as V51+ cells contained in or derived from either human tissues or the hematopoietic blood system or human tumors, respectively. All of the above cell types can be identified by their (i) location or where they originate, and (ii) their V51+ TCR expression.

[0067] A "modulatory antibody" is an antibody that, upon contact with or binding to a cell expressing a target to which the antibody binds, produces a measurable change, including but not limited to, a measurable change in cell cycle, and / or cell number, and / or cell viability, and / or one or more cell surface markers, and / or secretion of one or more secreted molecules (e.g., cytokines, chemokines, leukotrienes, etc.), and / or function (e.g., cytotoxicity towards target or diseased cells). A method of "modulating" a cell or population thereof refers to a method in which at least one measurable change in the cell or cells or secretions therefrom is induced to produce one or more "modulated cells."

[0068] An "immune response" is a measurable change in at least one cell, or one cell type, or one endocrine pathway, or one exocrine pathway of the immune system (including but not limited to, a cellular response, a humoral response, a cytokine response, or a chemokine response) upon addition of a regulatory antibody.

[0069] "Immune cells" are defined as cells of the immune system, including, but not limited to, CD34+ cells, B cells, CD45+ (lymphocyte common antigen) cells, αβ T cells, cytotoxic T cells, helper T cells, plasma cells, neutrophils, monocytes, macrophages, erythrocytes, platelets, dendritic cells, phagocytes, granulocytes, innate lymphoid cells, natural killer (NK) cells, and γδ T cells. Typically, combinatorial cell surface molecule analysis (e.g., by flow cytometry) is used to classify immune cells to identify them or to group or cluster them into distinct subpopulations, which can then be further subdivided by additional analyses. For example, CD45+ lymphocytes can be further subdivided into vδ-positive and vδ-negative populations.

[0070] A "model system" is a living model or biological representation designed to aid in understanding the extent to which a pharmaceutical agent, such as an antibody or antigen-binding fragment thereof, may function as a drug in ameliorating the signs or symptoms of a disease. Such models typically involve the use of in vitro, ex vivo, and in vivo diseased, non-diseased, healthy, effector cells, and tissues in which the performance of the agent can be studied and compared.

[0071] A "pathological cell" exhibits a phenotype associated with a disease such as cancer, an infection such as a viral infection, or the progression of an inflammatory condition or disease. For example, a pathological cell can be a tumor cell, an autoimmune tissue, or a virally infected cell. Thus, the pathological cell can be defined as tumorous, virally infected, or inflammatory.

[0072] "Healthy cells" refer to normal cells that are not affected by a disease. These may also be referred to as "normal" cells or "non-diseased" cells. Non-diseased cells include non-cancerous cells, or non-infected cells, or non-inflammatory cells. Such cells are often used in conjunction with related diseased cells to measure the diseased cell specificity exerted by a drug and / or to better understand the therapeutic index of a drug.

[0073] "Disease cell specificity" is a measure of how effective an effector cell or population thereof (e.g., a V51+ cell population) is at distinguishing and killing diseased cells, such as cancer cells, while sparing non-diseased or healthy cells. This ability can be measured in a model system and can involve comparing the tendency of an effector cell or effector cell population to selectively kill or lyse diseased cells to the ability of the effector cells to kill or lyse non-diseased or healthy cells. The diseased cell specificity can provide information about the potential therapeutic index of a drug.

[0074] "Enhanced disease cell specificity" refers to the phenotype of an effector cell, e.g., V51+ cell, or population thereof, that has been modulated to further enhance its ability to specifically kill disease cells. This enhancement can be measured in various ways, including the fold change or percent increase in specificity or selectivity of disease cell killing.

[0075] "ADCC" or "antibody-dependent cellular cytotoxicity" refers to an immune response against cells coated with antibodies that bind to cell surface antigens. It is a cell-mediated process in which immune effector cells (e.g., NK cells) recognize the cell-bound antibodies and cause degranulation and lysis of the target cells. Typically, this is mediated by Fc-Fcγ interactions. The Fc region of the cell-bound antibody recruits effector cells (e.g., NK cells) that express Fcγ receptors, causing degranulation of the effector cells and death of the target cells.

[0076] "Fc-enabled" refers to an antibody that contains a functional Fc region (fragment crystallizable region), i.e., an Fc region that has not been mutated or otherwise disabled. An Fc-enabled antibody exhibits unattenuated Fc function. An Fc-enabled antibody may contain a human IGHC heavy chain sequence listed in IMGT that has not been modified, engineered, or constructed to reduce binding to one or more Fcγ receptors. For example, through IGHC hinge mutations or by constructing an antibody containing a heavy chain constant domain that is a chimeric or hybrid of IgG1 / IgG2A or IgG1 / IgG4 IGHC sequences.

[0077] Preferably, the antibodies or antigen-binding fragments thereof (i.e., polypeptides) of the present invention are isolated. An "isolated" polypeptide is one that has been removed from its original environment. The term "isolated" may be used to refer to an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody or fragment thereof that specifically binds to Vδ1 is substantially free of antibodies that specifically bind to antigens other than Vδ1). The term "isolated" may also be used to refer to a preparation in which the isolated antibody is sufficiently pure to be administered therapeutically when formulated as the active ingredient of a pharmaceutical composition, or is at least 70-80% (w / w) pure, more preferably at least 80-90% (w / w) pure, even more preferably 90-95% pure, and most preferably at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) pure.

[0078] Preferably, the polynucleotide used in the present invention is isolated.An "isolated" polynucleotide is one that is removed from its original environment.For example, a naturally occurring polynucleotide is isolated if it is separated from some or all of the materials that coexist in natural system.For example, a polynucleotide is considered to be isolated if it is cloned into a vector that is not part of its natural environment, or if it is contained in cDNA.

[0079] An antibody or antigen-binding fragment thereof may be a "functionally active variant," including naturally occurring allelic variants, mutants, or any other non-naturally occurring variants. As known in the art, allelic variants are alternative forms of (poly)peptides characterized by one or more amino acid substitutions, deletions, or additions that do not essentially alter the biological function of the polypeptide. As non-limiting examples, such functionally active variants may still function if the framework containing the CDRs is modified, the CDRs themselves are modified, the CDRs are grafted onto alternative frameworks, or N- or C-terminal extensions are incorporated. Furthermore, CDR-containing binding domains may be paired with different partner chains, such as those shared with another antibody. The binding domains may still function if shared with a so-called "common" light chain or a "common" heavy chain. Furthermore, the binding domains may function when multimerized. Furthermore, "antibody or antigen-binding fragment thereof" can also include functional variants in which the VH or VL or constant domains have been altered away from or towards different canonical sequences (e.g., those listed at IMGT.org) and still function.

[0080] For comparing two closely related polypeptide sequences, the "% sequence identity" between a first polypeptide sequence and a second polypeptide sequence can be calculated using NCBI BLAST v2.0 with standard settings for polypeptide sequences (BLASTP). For comparing two closely related polynucleotide sequences, the "% sequence identity" between a first polynucleotide sequence and a second polynucleotide sequence can be calculated using NCBI BLAST v2.0 with standard settings for nucleotide sequences (BLASTN).

[0081] A polypeptide or polynucleotide sequence is said to be the same as, or "identical to," another polypeptide or polynucleotide sequence if they share 100% sequence identity over their entire length. Residues within a sequence are numbered from left to right, i.e., from N-terminus to C-terminus for polypeptides; from 5'-terminus to 3'-terminus for polynucleotides.

[0082] In some embodiments, any particular % sequence identity of a sequence is calculated without the sequences of all six CDRs of the antibody. For example, an anti-V51 antibody or antigen-binding fragment thereof may comprise a heavy chain variable region sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a particular heavy chain variable region sequence, and / or a light chain variable region sequence that is at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a particular light chain variable region sequence, wherein any amino acid diversity occurs only in the framework regions of the heavy and light chain variable region sequences. In such embodiments, an anti-V51 antibody or antigen-binding fragment thereof with a particular sequence identity retains the complete CDR1, CDR2, and CDR3 sequences of the heavy and light chains of the corresponding anti-V51 antibody or antigen-binding fragment thereof. A more specific example, which is in no way limiting and is intended solely to further illustrate these embodiments of the invention, provides an anti-V51 antibody or antigen-binding fragment thereof comprising a VH comprising, or consisting of, an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 15, and a VL comprising, or consisting of, an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 40, wherein any amino acid diversity occurs only in the framework regions of the heavy and light chain variable region sequences. Thus, the antibody of this exemplary embodiment further comprises a VHDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHDR2 comprising the amino acid sequence of SEQ ID NO: 53, a VHDR3 comprising the amino acid sequence of SEQ ID NO: 68, a VLDR1 comprising the amino acid sequence of SEQ ID NO: 79, a VLDR2 comprising the amino acid sequence of SEQ ID NO: 80, and a VLDR3 comprising the amino acid sequence of SEQ ID NO: 95.

[0083] Furthermore, the multispecific antibodies provided herein comprise a κ light chain variable sequence and may retain an amino acid residue other than serine at position 74 according to the IMGT numbering system, e.g., a non-polar and / or non-human germline residue, e.g., they may comprise a leucine residue at this position. For example, and by no means limiting, and merely to further illustrate these embodiments of the invention, there is provided an anti-Vδ1 antibody or antigen-binding fragment thereof comprising a VH comprising, or consisting of, an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 15, and a VL comprising, or consisting of, an amino acid sequence at least 90% identical to the amino acid sequence of SEQ ID NO: 40, wherein any amino acid diversity occurs only in the framework regions of the heavy and light chain variable region sequences, and wherein the antibody comprises a κ light chain variable sequence comprising an amino acid residue at position 74 according to the IMGT numbering system that is non-human germline and / or non-polar (e.g., a leucine residue at this position). The antibody of this specific example further comprises a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 68, a VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, a VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 95.

[0084] A "difference" between sequences refers to the insertion, deletion, or substitution of a single amino acid residue at a position in a second sequence compared to a first sequence. Two polypeptide sequences can contain one, two, or more such amino acid differences. An insertion, deletion, or substitution in a second sequence that is otherwise identical to a first sequence (100% sequence identity) results in a decrease in the percent sequence identity. For example, if an identical sequence is 9 amino acid residues long, a single substitution in the second sequence results in 88.9% sequence identity. If a first polypeptide sequence and a second polypeptide sequence are 9 amino acid residues long and share six identical residues, the first polypeptide sequence and the second polypeptide sequence share more than 66% identity (the first polypeptide sequence and the second polypeptide sequence share 66.7% identity).

[0085] Alternatively, to compare a first reference polypeptide sequence with a second comparison polypeptide sequence, the number of additions, substitutions, and / or deletions made to the first sequence to generate the second sequence can be determined. An "addition" is the addition of one amino acid residue to the sequence of the first polypeptide (including additions at either end of the first polypeptide). A "substitution" is the replacement of one amino acid residue in the sequence of the first polypeptide with a different amino acid residue. Such substitutions can be conservative or non-conservative. A "deletion" is the removal of one amino acid residue from the sequence of the first polypeptide (including deletions at either end of the first polypeptide).

[0086] Using the three-letter and one-letter codes, naturally occurring amino acids can be designated as follows: glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), proline (P or Pro), phenylalanine (F or Phe), tyrosine (Y or Tyr), tryptophan (W or Trp), lysine (K or Lys), arginine (R or Arg), histidine (H or His), aspartic acid (D or Asp), glutamic acid (E or Glu), asparagine (N or Asn), glutamine (Q or Gln), cysteine ​​(C or Cys), methionine (M or Met), serine (S or Ser), and threonine (T or Thr). When the residue can be aspartic acid or asparagine, the symbols Asx or B can be used. Where the residue may be any amino acid, the symbol Xaa or X may be used. Where the residue may be glutamic acid or glutamine, the symbol Glx or Z may be used. Unless the context dictates otherwise, a reference to aspartic acid includes aspartate and a reference to glutamic acid includes glutamate.

[0087] As used herein, the numbering of polypeptide sequences and the definitions of CDRs and FRs are as defined according to the EU and / or IMGT numbering system, as indicated by the context. "Corresponding" amino acid residues between a first polypeptide sequence and a second polypeptide sequence are amino acid residues in the first sequence that share the same position as the amino acid residues in the second sequence according to the EU and / or IMGT numbering system, as indicated by the context, but the amino acid residues in the second sequence may differ in identity from the first sequence. Preferably, corresponding residues share the same number (and letter) when the framework and CDRs are the same length according to the EU or IMGT definition. Alignment can be achieved manually or by using known computer algorithms for sequence alignment, such as, for example, NCBI BLAST v2.0 (BLASTP or BLASTN) using standard settings.

[0088] References to "epitope" herein refer to the portion of a target that is specifically bound by an antibody or its antigen-binding fragment. An epitope can also be referred to as an "antigenic determinant." An antibody binds to "essentially the same epitope" as another antibody when they both recognize the same or sterically overlapping epitopes. A commonly used method for determining whether two antibodies bind to the same or overlapping epitopes is a competitive assay, which can be configured in a number of different formats using either labeled antigen or labeled antibody (e.g., well plates using radioactive or enzyme labels, or flow cytometry on cells expressing the antigen). An antibody binds to the "same epitope" as another antibody when they both recognize the same epitope (i.e., all contact points between the antigen and the antibody are the same).

[0089] Epitopes found in protein targets can be defined as "linear epitopes" or "conformational epitopes." Linear epitopes are formed by contiguous sequences of amino acids in the protein antigen. Conformational epitopes are formed from amino acids that are discontinuous within the protein sequence but are brought together when the protein folds into a three-dimensional structure.

[0090] As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, into which additional DNA segments can be ligated. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian and yeast vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors." In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As the plasmid is the most commonly used form of vector, "plasmid" and "vector" may be used interchangeably herein. However, the invention is intended to encompass other forms of expression vectors, such as viral vectors (e.g., replication-defective retroviruses, adenoviruses, and adeno-associated viruses), and even bacteriophage and phagemid systems, which serve equivalent functions. As used herein, the term "recombinant host cell" (or simply "host cell") is intended to refer to a cell into which a recombinant expression vector has been introduced. Such terms are intended to refer not only to the particular subject cell, but also to progeny of such cells, for example, when used to create cell lines or cell banks that are then optionally stored, provided, sold, given away, or used to produce antibodies or antigen-binding fragments thereof described herein.

[0091] Reference to a "subject," "patient," or "individual" refers to a subject to be treated, particularly a mammalian subject. Mammalian subjects include humans, non-human primates, farm animals (e.g., cows), sport animals, or pets, such as dogs, cats, guinea pigs, rabbits, rats, or mice. In some embodiments, the subject is a human. In alternative embodiments, the subject is a non-human mammal, such as a mouse.

[0092] The term "sufficient amount" means an amount sufficient to cause a desired effect. The term "therapeutically effective amount" is an amount effective to ameliorate the symptoms of a disease or disorder. A therapeutically effective amount can be a "prophylactically effective amount" where prevention can be considered treatment.

[0093] A disease or disorder is "alleviated" if the severity of a sign or symptom of the disease or disorder, the frequency with which such sign or symptom is experienced by a subject, or both, are reduced (compared to an earlier time point, e.g., before administration of any antibody).

[0094] As used herein, "treating a disease or disorder" means reducing the frequency and / or severity of at least one sign or symptom of the disease or disorder experienced by a subject (compared to an earlier time point, e.g., before administration of any antibody).

[0095] As used herein, "cancer" refers to the abnormal growth or division of cells. Generally, the growth and / or lifespan of cancer cells exceeds and is uncoordinated with the growth and / or lifespan of surrounding normal cells and tissues. Cancers can be benign, pre-malignant, or malignant. Cancers arise in a variety of cells and tissues, including the oral cavity (e.g., mouth, tongue, pharynx, etc.), digestive system (e.g., esophagus, stomach, small intestine, colon, rectum, liver, bile duct, gallbladder, pancreas, etc.), respiratory system (e.g., larynx, lungs, bronchi, etc.), bones, joints, skin (e.g., basal cell, squamous cell, meningioma, etc.), breast, reproductive system (e.g., uterus, ovaries, prostate, testes, etc.), urinary system (e.g., bladder, kidneys, ureters, etc.), eyes, nervous system (e.g., brain, etc.), endocrine system (e.g., thyroid, etc.), and hematopoietic system (e.g., lymphoma, myeloma, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, etc.).

[0096] As used herein, the term "about" as used herein includes up to 10% above and below the specified value, preferably up to 5% above and below the specified value, and particularly includes the specified value. The term "between" includes the boundary values ​​specified.

[0097] Multispecific antibodies and antigen-binding fragments thereof Provided herein are multispecific antibodies capable of specifically binding to the delta variable 1 chain (V51) of the gamma delta T cell receptor (TCR) and also capable of specifically binding to EGFR. The present invention relates to the use of said antibodies as medicaments for administration to a subject to be treated.

[0098] In one embodiment, the antibody or antigen-binding fragment thereof is an scFv, Fab, Fab', F(ab'), Fv, a variable domain (e.g., VH or VL), a diabody, a minibody, or a monoclonal antibody. In a further embodiment, the antibody or antigen-binding fragment thereof is an scFv.

[0099] The multispecific antibodies of the present invention can be of any class, e.g., IgG, IgA, IgM, IgE, IgD, or their isotypes, and can contain a κ or λ light chain. In one embodiment, the antibody is an IgG antibody, e.g., at least one of the isotypes IgG1, IgG2, IgG3, or IgG4. In further embodiments, the antibody can be in a format, such as an IgG format, with an Fc mutated to confer desired properties, e.g., to reduce effector function, extend half-life, alter ADCC, or improve hinge stability. Such modifications are well known in the art.

[0100] In one embodiment, the antibody or antigen-binding fragment thereof is human. Thus, the antibody or antigen-binding fragment thereof may be derived from a human immunoglobulin (Ig) sequence. The CDRs, framework, and / or constant regions of the antibody (or antigen-binding fragment thereof) may be derived from a human Ig sequence, particularly a human IgG sequence. The CDRs, framework, and / or constant regions may be substantially identical to the human Ig sequence, particularly a human IgG sequence. The advantage of using human antibodies is that they are less immunogenic or non-immunogenic in humans.

[0101] The antibody or antigen-binding fragment thereof may be chimeric, for example, a mouse / human chimeric antibody.

[0102] Alternatively, the antibody or antigen-binding fragment thereof is derived from a non-human species, such as mouse. Such non-human antibodies can be modified to increase their similarity to antibody variants naturally produced in humans, thereby making the antibody or antigen-binding fragment thereof partially or fully humanized. Thus, in one embodiment, the antibody or antigen-binding fragment thereof is humanized.

[0103] Summary of specific Fab regions provided herein A summary of some of the specific antigen-binding molecules (i.e., antibodies) used in the present invention is provided below, along with the assigned SEQ ID NOs in the accompanying sequence listing. Antigen-binding variants, derivatives, and fragments thereof are also provided as part of the present invention. The sequences are shown in the accompanying sequence listing and in the accompanying figures. In the event of discrepancies between the sequences in the sequence listing and those in Figures 22-25, the sequences in the figures shall prevail. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0104] Fab regions derived from ADT1-4 and ADT1-7 The present invention provides multispecific antibodies whose Fab regions are derived from the parent antibody ADT1-4 (having a heavy chain variable region sequence set forth in SEQ ID NO: 1 and a light chain variable region sequence set forth in SEQ ID NO: 26), and antibodies derived from the parent antibody ADT1-7 (having a heavy chain variable region sequence set forth in SEQ ID NO: 106 and a light chain variable region sequence set forth in SEQ ID NO: 118). ADT1-4 is also referred to herein as G04, and ADT1-4 and G04 are used interchangeably. ADT1-7 is also referred to herein as E07, and ADT1-7 and E07 are used interchangeably.

[0105] In some embodiments, the invention provides a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising, or consisting of, a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 55 to 78 and 133 to 143; and / or a light chain variable region comprising, or consisting of, a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 82 to 105 and 147 to 157. Certain amino acid substitutions can be made to provide one or more of the variant antibodies described herein.

[0106] In some embodiments, the invention provides a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a VHCDR1 comprising or consisting of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 51, 52, and 130; a VHCDR2 comprising or consisting of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 53 and 131; and A heavy chain variable region comprising a VHCDR3 comprising or consisting of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 55-78 and 133-143; and VLCDR1 comprising or consisting of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 79 and 144; a VLCDR2 comprising or consisting of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 80 and 145; and A light chain variable region comprising a VLCDR3 comprising or consisting of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 82 to 105 and 147 to 157.

[0107] Certain amino acid substitutions can be made to provide one or more of the variant Fab regions described herein.

[0108] In some embodiments, the invention provides a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 2-25 and 107-117; and / or A light chain variable region comprising, or consisting of, a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 27 to 50 and 119 to 129.

[0109] Fab region derived from ADT1-4 The present invention provides multispecific antibodies comprising Fab regions derived from parent antibody ADT1-4 (having a heavy chain variable region sequence set forth in SEQ ID NO: 1 and a light chain variable region sequence set forth in SEQ ID NO: 26), for example as described below. ADT1-4 is also referred to herein as G04, and ADT1-4 and G04 are used interchangeably.

[0110] Antibodies containing specific CDR sequences derived from ADT1-4 The multispecific antibodies provided herein comprise the following Fab regions having specific sequences derived from ADT1-4:

[0111] For example, in some embodiments, multispecific antibodies are provided in which the anti-TCRδ variable region 1 (anti-Vδ1) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising, or consisting of, an amino acid sequence selected from the group consisting of SEQ ID NOs: 55 to 78; and / or a light chain variable region comprising a VL CDR3 comprising, or consisting of, an amino acid sequence selected from the group consisting of SEQ ID NOs: 82 to 105. Certain amino acid substitutions can be made to provide one or more of the variant antibodies described herein.

[0112] In some embodiments, multispecific antibodies are provided, wherein the anti-TCRδ variable region 1 (anti-Vδ1) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising, or consisting of, an amino acid sequence selected from the group consisting of SEQ ID NOs: 55 to 77; and / or a light chain variable region comprising a VL CDR3 comprising, or consisting of, an amino acid sequence selected from the group consisting of SEQ ID NOs: 82 to 104. Certain amino acid substitutions can be made to provide one or more of the variant antibodies described herein.

[0113] In some embodiments, multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising, or consisting of, an amino acid sequence selected from the group consisting of SEQ ID NOs: 58, 60, 61, 62, 65, 66, 68, 74, 76, and 77; and / or a light chain variable region comprising a VL CDR3 comprising, or consisting of, an amino acid sequence selected from the group consisting of SEQ ID NOs: 85, 87, 88, 89, 92, 93, 95, 101, 103, and 104. Certain amino acid substitutions may be made to provide one or more of the variant antibodies described herein.

[0114] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 51 and 52; VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 53; and A heavy chain variable region comprising a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 55 to 78, and VLCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 79; VLCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 80; and A light chain variable region comprising a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 82 to 105. Certain amino acid substitutions can be made to provide one or more of the variant antibodies described herein.

[0115] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 51 and 52; VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 53; and A heavy chain variable region comprising a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 55 to 77, and VLCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 79; VLCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 80; and A light chain variable region comprising a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 82 to 104. Certain amino acid substitutions can be made to provide one or more of the variant antibodies described herein.

[0116] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 51 and 52; VHCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 53; and a heavy chain variable region comprising a VHCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 58, 60, 61, 62, 65, 66, 68, 74, 76, and 77; and VLCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 79; VLCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 80; and A light chain variable region comprising a VLCDR3 comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 85, 87, 88, 89, 92, 93, 95, 101, 103, and 104.

[0117] Certain amino acid substitutions can be made to provide one or more of the variant antibodies described herein.

[0118] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 55, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 82, respectively; b) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 56, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 83, respectively; c) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 57, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 84, respectively; d) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 58, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 85, respectively; e) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 59, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 86, respectively; f) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 60, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 87, respectively; g) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 52, 53, and 61, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 88, respectively; h) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 62, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 89, respectively; i) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 63, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 90, respectively; j) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 64, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 91, respectively; k) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 65, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 92, respectively; l) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 52, 53, and 66, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 93, respectively; m) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 67, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 94, respectively; n) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 68, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 95, respectively; o) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 69, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 96, respectively; p) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 70, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 97, respectively; q) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 71, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 98, respectively; r) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 72, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 99, respectively; s) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 73, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 100, respectively; t) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 52, 53, and 74, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 101, respectively; u) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 75, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 102, respectively; v) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 76, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 103, respectively; w) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 77, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 104, respectively; or x) VHCDR1, VHCDR2, and VHCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 51, 53, and 78, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 79, 80, and 105, respectively.

[0119] The multispecific antibody can comprise a κ light chain variable sequence (or comprise a variable light chain derived from a κ light chain variable sequence), wherein residue 74 of said κ light chain variable sequence according to the IMGT numbering system is not a serine, e.g., a non-human germline residue at position 74 and / or a non-polar residue, e.g., residue 74 is a leucine residue.

[0120] Further embodiments are provided below.

[0121] ADT1-4-105 and its fragments and variants Certain embodiments relate to the antibody ADT1-4-105 and fragments and variants thereof.

[0122] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 55, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 82. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 55, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 82. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 55, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 82.

[0123] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-105, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 55, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 82, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0124] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 55; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 82, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 82.

[0125] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 55; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 82.

[0126] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 55; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:82.

[0127] Amino acid substitutions can be made to provide variant antibodies with Fab regions derived from ADT1-4-105, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 55, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 82, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0128] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0129] ADT1-4-107 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-107 and fragments and variants thereof.

[0130] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 56, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 83. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 56, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 83. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 56, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 83.

[0131] Amino acid substitutions can be made to provide variant antibodies comprising a Fab region derived from ADT1-4-107, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 56, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 83, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0132] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 56; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 83, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 83.

[0133] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 56; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 83.

[0134] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 56; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 83.

[0135] Amino acid substitutions can be made to provide variant antibodies comprising a Fab region derived from ADT1-4-107, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 56, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 83, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0136] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0137] ADT1-4-110 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-110 and fragments and variants thereof.

[0138] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 57, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 84. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 57, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 84. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 57, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 84.

[0139] Amino acid substitutions can be made to provide variant antibodies comprising a Fab region derived from ADT1-4-110, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 57, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 84, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0140] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 57; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 84, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 84.

[0141] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 57; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 84.

[0142] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 57; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:84.

[0143] Amino acid substitutions can be made to provide variant antibodies comprising a Fab region derived from ADT1-4-110, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 57, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 84, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0144] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0145] ADT1-4-112 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-112 and fragments and variants thereof.

[0146] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 58, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 85. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 58, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 85. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 58, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 85.

[0147] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-112, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 58, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 85, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0148] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 58; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 85, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 85.

[0149] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 58; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 85.

[0150] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 58; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 85.

[0151] Amino acid substitutions can be made to provide variant antibodies with Fab regions derived from ADT1-4-112, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 58, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 85, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0152] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0153] ADT1-4-117 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-117 and fragments and variants thereof.

[0154] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 59, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 86. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 59, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 86. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 59, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 86.

[0155] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-117, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 59, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 86, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0156] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 59; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 86, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 86.

[0157] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 59; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 86.

[0158] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 59; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:86.

[0159] Amino acid substitutions can be made to provide variant antibodies with Fab regions derived from ADT1-4-117, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 59, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 86, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0160] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0161] ADT1-4-19 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-19 and fragments and variants thereof.

[0162] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 60, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 87. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 60, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 87. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 60, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 87.

[0163] Amino acid substitutions can be made to provide variant antibodies comprising a Fab region derived from ADT1-4-19, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 60, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 87, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0164] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 60; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 87, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 87.

[0165] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 60; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 87.

[0166] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 60; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:87.

[0167] Amino acid substitutions can be made to provide variant antibodies with Fab regions derived from ADT1-4-19, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 60, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 87, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0168] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0169] ADT1-4-21 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-21 and fragments and variants thereof.

[0170] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 61, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 88. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 61, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 88. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 61, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 88.

[0171] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-21, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 61, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 88, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0172] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 52, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 61; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 88, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 88.

[0173] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 52, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 61; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 88.

[0174] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 61; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:88.

[0175] Amino acid substitutions can be made to provide variant antibodies comprising a Fab region derived from ADT1-4-21, for example, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 52, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 61, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 88, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0176] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0177] ADT1-4-31 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-31 and fragments and variants thereof.

[0178] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 62, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 89. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 62, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 89. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 62, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 89.

[0179] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-31, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 62, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 89, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0180] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 62; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:89; and VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:89.

[0181] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 62; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 89.

[0182] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 62; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:89.

[0183] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-31, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 62, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 89, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0184] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0185] ADT1-4-139 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-139 and fragments and variants thereof.

[0186] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 63, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 90. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 63, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 90. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 63, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 90.

[0187] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-139, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 63, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 90, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0188] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 63; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 90, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 90.

[0189] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 63; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 90.

[0190] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 63; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 90.

[0191] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-139, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 63, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 90, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0192] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0193] ADT1-4-4 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-4 and fragments and variants thereof.

[0194] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 64, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 91. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 64, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 91. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 64, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 91.

[0195] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-4, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 64, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 91, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0196] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 64; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:91, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:91.

[0197] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 64; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 91.

[0198] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 64; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 91.

[0199] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-4, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 64, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 91, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0200] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0201] ADT1-4-143 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-143 and fragments and variants thereof.

[0202] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 65, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 92. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 65, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 92. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 65, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 92.

[0203] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-143, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 65, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 92, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0204] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 65; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:92, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:92.

[0205] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 65; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 92.

[0206] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 65; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 92.

[0207] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-143, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 65, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 92, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0208] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0209] ADT1-4-53 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-53 and fragments and variants thereof.

[0210] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 66, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 93. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 66, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 93. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 66, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 93.

[0211] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-53, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 66, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 93, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0212] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 52, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 66; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:93, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:93.

[0213] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 52, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 66; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 93.

[0214] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 66; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 93.

[0215] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-53, for example, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 52, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 66, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 93, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0216] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0217] ADT1-4-173 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-173 and fragments and variants thereof.

[0218] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 67, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 94. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 67, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 94. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 67, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 94.

[0219] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-173, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 67, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 94, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0220] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 67; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:94, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:94.

[0221] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 67; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 94.

[0222] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 67; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 94.

[0223] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-173, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 67, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 94, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0224] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0225] ADT1-4-2 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-2 and fragments and variants thereof.

[0226] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 68, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 95. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 68, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 95. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 68, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 95.

[0227] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-2, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 68, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 95, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0228] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 68; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:95, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:95.

[0229] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 68; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 95.

[0230] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 68; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 95.

[0231] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-2, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 68, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 95, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0232] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0233] ADT1-4-8 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-8 and fragments and variants thereof.

[0234] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 69, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 96. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 69, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 96. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 69, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 96.

[0235] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-8, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 69, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 96, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0236] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 69; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:96, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:96.

[0237] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 69; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 96.

[0238] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 69; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:96.

[0239] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-8, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 69, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 96, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0240] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0241] ADT1-4-82 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-82 and fragments and variants thereof.

[0242] For example, in some embodiments multispecific antibodies are provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 70, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 97. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 70, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 97. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 70, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0243] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-82, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 70, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 97, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0244] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 70; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:97, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:97.

[0245] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 70; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 97.

[0246] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 70; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:97.

[0247] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-82, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 70, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 97, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0248] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0249] ADT1-4-83 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-83 and fragments and variants thereof.

[0250] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 71, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 98. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 71, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 98. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 71, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 98.

[0251] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-83, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 71, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 98, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0252] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 71; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:98; and VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:98.

[0253] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 71; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 98.

[0254] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 71; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:98.

[0255] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-83, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 71, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 98, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0256] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0257] ADT1-4-3 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-3 and fragments and variants thereof.

[0258] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 72, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 99. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 72, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 99. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 72, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 99.

[0259] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-3, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 72, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 99, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0260] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 72; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 99, a light chain variable region comprising a VLCDR2 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO:99.

[0261] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 72; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 99.

[0262] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 72; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO:79, VLCDR2 comprising the amino acid sequence of SEQ ID NO:80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO:99.

[0263] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-3, for example, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 72, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 99, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0264] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0265] ADT1-4-84 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-84 and fragments and variants thereof.

[0266] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 73, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 73, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 100. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 73, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 100.

[0267] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-84, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 73, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 100, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0268] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 73; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , a VLCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 100.

[0269] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 73; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 100.

[0270] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 73; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 100.

[0271] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-84, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 73, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 100, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0272] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0273] ADT1-4-86 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-86 and fragments and variants thereof.

[0274] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 74, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 101. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 74, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 101. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 74, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 101.

[0275] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-86, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 74, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 101, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0276] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 52, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 74; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 101, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 101.

[0277] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 52, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 74; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 101.

[0278] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 74; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 101.

[0279] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-86, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 52, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 74, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 101, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0280] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0281] ADT1-4-95 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-95 and fragments and variants thereof.

[0282] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 75, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 102. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 75, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 102. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 75, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 102.

[0283] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-95, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 75, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 102, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0284] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 75; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 102, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 102.

[0285] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 75; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 102.

[0286] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 75; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 102.

[0287] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-95, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 75, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 102, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0288] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0289] ADT1-4-1 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-1 and fragments and variants thereof.

[0290] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 76, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 103. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 76, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 103. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 76, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 103.

[0291] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-1, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 76, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 103, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0292] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 76; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 103, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 103.

[0293] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 76; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 103.

[0294] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 76; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 103.

[0295] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-1, for example, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 76, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 103, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0296] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0297] ADT1-4-6 and fragments and variants thereof Particular embodiments relate to the antibody ADT1-4-6 and fragments and variants thereof.

[0298] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 77, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 104. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 77, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 104. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 77, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 104.

[0299] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-6, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 77, optionally comprising one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 104, optionally comprising one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0300] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 77; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 104, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 104.

[0301] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 77; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 104.

[0302] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 77; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 104.

[0303] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-6, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 77, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 104, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0304] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0305] ADT1-4-138 and its fragments and variants Particular embodiments relate to the antibody ADT1-4-138 and fragments and variants thereof.

[0306] For example, in some embodiments, a multispecific antibody is provided, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 78, and / or a light chain variable region comprising a VL CDR3 comprising an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 105. In one embodiment, an antibody or antigen-binding fragment or variant thereof is provided, comprising a heavy chain variable region comprising a VHCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 78, and / or a light chain variable region comprising a VLCDR3 comprising an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 105. In one embodiment, a multispecific antibody is provided, wherein an anti-TCR delta variable region 1 (anti-V51)-binding Fab region comprises a heavy chain variable region comprising a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 78, and / or a light chain variable region comprising a VLCDR3 comprising the amino acid sequence of SEQ ID NO: 105.

[0307] Amino acid substitutions can be made to provide variant antibodies having a Fab region derived from ADT1-4-138, for example multispecific antibodies are provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises a heavy chain variable region comprising a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 78, optionally containing one or two amino acid substitutions, and / or a light chain variable region comprising a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 105, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0308] In some embodiments there is provided a multispecific antibody wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: VHCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 51, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 53 a heavy chain variable region comprising a VHCDR2 that comprises at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity, and a VHCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 78; and / or VLCDR1 comprising at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 79, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93% identity to the amino acid sequence of SEQ ID NO: 80 , at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 105, and a VLCDR3 that comprises at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 105.

[0309] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 78; and / or A light chain variable region comprising VLCDR1 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising at least 90% identity to the amino acid sequence of SEQ ID NO: 105.

[0310] In one embodiment, a multispecific antibody is provided in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 78; and A light chain variable region comprising VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 105.

[0311] Amino acid substitutions can be made to provide variant antibodies having Fab regions derived from ADT1-4-138, for example, to provide a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising a VHCDR1 comprising the amino acid sequence of SEQ ID NO: 51, optionally containing one or two amino acid substitutions, a VHCDR2 comprising the amino acid sequence of SEQ ID NO: 53, optionally containing one or two amino acid substitutions, and a VHCDR3 comprising the amino acid sequence of SEQ ID NO: 78, optionally containing one or two amino acid substitutions; and / or A light chain variable region comprising: VLCDR1 comprising the amino acid sequence of SEQ ID NO: 79, optionally containing one or two amino acid substitutions; VLCDR2 comprising the amino acid sequence of SEQ ID NO: 80, optionally containing one or two amino acid substitutions; and VLCDR3 comprising the amino acid sequence of SEQ ID NO: 105, optionally containing one or two amino acid substitutions. The amino acid substitutions may be conservative amino acid substitutions.

[0312] Alternatively, the antibody may consist of the specified sequence (with or without amino acid substitutions).

[0313] Antibodies comprising heavy chain variable regions and / or light chain variable regions derived from ADT1-4 Provided herein is a multispecific antibody, wherein the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 2-25; and / or A light chain variable region comprising, or consisting of, a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 27 to 50.

[0314] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 2-24; and / or A light chain variable region comprising, or consisting of, a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 27 to 49.

[0315] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 7, 8, 9, 12, 13, 15, 21, 23, and 24; and / or A light chain variable region comprising, or alternatively consisting of, a sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to a sequence selected from the group consisting of SEQ ID NOs: 30, 32, 33, 34, 37, 38, 40, 46, 48, and 49.

[0316] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NOs: 2 to 25; and / or A light chain variable region comprising or consisting of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NOs: 27 to 50.

[0317] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NOs: 2 to 24; and / or A light chain variable region comprising or consisting of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NOs: 27 to 49.

[0318] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NOs: 5, 7, 8, 9, 12, 13, 15, 21, 23, and 24; and / or A light chain variable region comprising or consisting of a sequence having at least 90% identity to a sequence selected from the group consisting of SEQ ID NOs: 30, 32, 33, 34, 37, 38, 40, 46, 48, and 49.

[0319] Optionally, the above antibodies retain the corresponding CDR sequences, so that any diversity in the VH and VL sequences occurs in the framework regions.

[0320] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence selected from the group consisting of SEQ ID NOs: 2 to 25; and / or A light chain variable region comprising or consisting of a sequence selected from the group consisting of SEQ ID NOs: 27 to 50.

[0321] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain variable region comprising or consisting of a sequence selected from the group consisting of SEQ ID NOs: 2 to 24; and / or A light chain variable region comprising or consisting of a sequence selected from the group consisting of SEQ ID NOs: 27 to 49.

[0322] Also provided is a multispecific antibody in which the anti-TCR delta variable region 1 (anti-V51) binding Fab region comprises: a heavy chain ...

Claims

1. 1. A multispecific antibody comprising a Fab region and an Fc region, wherein the Fab region comprises a binding site specific for an epitope of the variable δ1 (Vδ1) chain of the γδ T cell receptor (TCR) and the Fc region comprises an EGFR binding site.

2. The EGFR binding site is a. residues 359-362 (EU numbering) constitute EEGP (SEQ ID NO:523), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); or b. residues 359-362 (EU numbering) constitute EEGP (SEQ ID NO:523) and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); or c. residues 359-362 (EU numbering) constitute EEGP (SEQ ID NO:523), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-415 (EU numbering) constitute SYW (SEQ ID NO:533); or d. residues 358-361, 361.1 and 362 (EU numbering) constitute LDEGGP (SEQ ID NO:542), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-419 (EU numbering) constitute SYWRWVK (SEQ ID NO:543); or e. residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511) and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); f. residues 358-362 (EU numbering) constitute TDDGP (SEQ ID NO:560), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); or g. residues 358-362 (EU numbering) comprise TESGP (SEQ ID NO:553), residues 384-386 (EU numbering) comprise KFG (SEQ ID NO:554), residues 413-421 (EU numbering) comprise SNLRWTKGH (SEQ ID NO:555), and residue 378 is a valine; h. residues 355-362 (EU numbering) form an AB loop comprising RDELEEGP (SEQ ID NO:524), residues 383-391 (EU numbering) form a CD loop comprising STYGPENNY (SEQ ID NO:514), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO:515); or i. residues 355-362 (EU numbering) form an AB loop comprising RDELEEGP (SEQ ID NO:524), residues 383-391 (EU numbering) form a CD loop comprising SNGQPENNY (SEQ ID NO:525), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO:515); or j. residues 355-362 (EU numbering) form the AB loop comprising RDELEEGP (SEQ ID NO:524), residues 383-391 (EU numbering) form the CD loop comprising STYGPENNY (SEQ ID NO:514), and residues 413-422 (EU numbering) form the EF loop comprising SYWRWQQGNV (SEQ ID NO:534); or k. residues 355-362 (EU numbering) form an AB loop comprising RDELDEGGP (SEQ ID NO:544), residues 383-391 (EU numbering) form a CD loop comprising STYGPENNY (SEQ ID NO:514), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWVKGNV (SEQ ID NO:545); or l. residues 355-362 (EU numbering) form an AB loop comprising RDELTKNQ (SEQ ID NO:513), residues 383-391 (EU numbering) form a CD loop comprising STYGPENNY (SEQ ID NO:514), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO:515); or m. residues 355-362 (EU numbering) form an AB loop comprising RDETDDGP (SEQ ID NO:561), residues 383-391 (EU numbering) form a CD loop comprising STYGPENNY (SEQ ID NO:514), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO:515); or n. The multispecific antibody of claim 1, wherein residues 355-362 (EU numbering) form an AB loop comprising RDETESGP (SEQ ID NO:556), residues 383-391 (EU numbering) form a CD loop comprising SKFGPENNY (SEQ ID NO:557), residues 413-422 (EU numbering) form an EF loop comprising SNLRWTKGHV (SEQ ID NO:558), and residue 378 is provided by the CH3 domain which is a valine.

3. The EGFR binding site, a. residues 359-362 (EU numbering) constitute EEGP (SEQ ID NO:523), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); or b. residues 359-362 (EU numbering) constitute EEGP (SEQ ID NO:523) and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); or c. residues 359-362 (EU numbering) constitute EEGP (SEQ ID NO:523), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-415 (EU numbering) constitute SYW (SEQ ID NO:533); or d. residues 355-362 (EU numbering) form an AB loop comprising RDELEEGP (SEQ ID NO:524), residues 383-391 (EU numbering) form a CD loop comprising STYGPENNY (SEQ ID NO:514), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO:515); or e. residues 355-362 (EU numbering) form an AB loop comprising RDELEEGP (SEQ ID NO:524), residues 383-391 (EU numbering) form a CD loop comprising SNGQPENNY (SEQ ID NO:525), and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO:515); or f. The multispecific antibody of claim 2, wherein residues 355-362 (EU numbering) form the AB loop comprising RDELEEGP (SEQ ID NO: 524), residues 383-391 (EU numbering) form the CD loop comprising STYGPENNY (SEQ ID NO: 514), and residues 413-422 (EU numbering) form the EF loop comprising SYWRWQQGNV (SEQ ID NO: 534) provided by the CH3 domain.

4. The EGFR binding site is a. residues 358-362 (EU numbering) constitute TDDGP (SEQ ID NO:560), residues 384-386 (EU numbering) constitute TYG (SEQ ID NO:511), and residues 413-419 (EU numbering) constitute SYWRWYK (SEQ ID NO:512); or b. A multispecific antibody according to any of claims 1 to 3, which is not provided by a CH3 domain, in which residues 355-362 (EU numbering) form an AB loop comprising RDETDDGP (SEQ ID NO: 561), residues 383-391 (EU numbering) form a CD loop comprising STYGPENNY (SEQ ID NO: 514) and residues 413-422 (EU numbering) form an EF loop comprising SYWRWYKGNV (SEQ ID NO: 515).

5. The multispecific antibody of claim 1 , wherein the CH3 domain is a human IgG CH3 domain engineered to contain the EGFR binding site.

6. The multispecific antibody of claim 2 or 3, wherein the Fc region is a human IgG Fc region comprising the CH3 domain engineered to contain the EGFR binding site.

7. The amino acid sequence of the CH3 domain is a. SEQ ID NO:562; b. SEQ ID NO:522; c. SEQ ID NO:532; d. SEQ ID NO:541; e. SEQ ID NO:510; f. SEQ ID NO:559; or g. SEQ ID NO:552 The multispecific antibody of any of claims 1 to 6, which is at least 90% identical, or at least 95% identical, or 100% identical to

8. The amino acid sequence of the CH3 domain is a. SEQ ID NO:562; b. SEQ ID NO:522; or c. SEQ ID NO:532; 8. The multispecific antibody of claim 7, which is at least 90% identical, or at least 95% identical, or 100% identical to

9. The multispecific antibody of any one of claims 1 to 8, wherein the antibody is Fc-enabled.

10. The Fc region is a. SEQ ID NO:391 or SEQ ID NO:392; b. SEQ ID NO:520 or SEQ ID NO:521; c. SEQ ID NO:530 or SEQ ID NO:531; d. SEQ ID NO:539 or SEQ ID NO:540; e. SEQ ID NO:508 or SEQ ID NO:509; f. SEQ ID NO:385 or SEQ ID NO:386; or g. SEQ ID NO: 550 or SEQ ID NO: 551 The multispecific antibody according to any one of claims 1 to 9, comprising:

11. The Fc region comprises: a. SEQ ID NO:391 or SEQ ID NO:392; b. SEQ ID NO:520 or SEQ ID NO:521; c. SEQ ID NO:530 or SEQ ID NO:531; or d. SEQ ID NO:508 or SEQ ID NO:509; The multispecific antibody of claim 10, comprising:

12. a. SEQ ID NO:389; or SEQ ID NO:414 and SEQ ID NO:432; b. SEQ ID NO:400; or SEQ ID NO:414 and SEQ ID NO:436; c. SEQ ID NO:516; or SEQ ID NO:414 and SEQ ID NO:518; d. SEQ ID NO:517; or SEQ ID NO:414 and SEQ ID NO:519; e. SEQ ID NO:526; or SEQ ID NO:414 and SEQ ID NO:528; f. SEQ ID NO:527; or SEQ ID NO:414 and SEQ ID NO:529; g. SEQ ID NO:535; or SEQ ID NO:414 and SEQ ID NO:537; h. SEQ ID NO:536; or SEQ ID NO:414 and SEQ ID NO:538; i. SEQ ID NO:504; or SEQ ID NO:414 and SEQ ID NO:506; j. SEQ ID NO:505; or SEQ ID NO:414 and SEQ ID NO:507; k. SEQ ID NO:388; or SEQ ID NO:414 and SEQ ID NO:431; l. SEQ ID NO:399; or SEQ ID NO:414 and SEQ ID NO:435; m. SEQ ID NO:546; or SEQ ID NO:414 and SEQ ID NO:548; n. SEQ ID NO:547; or SEQ ID NO:414 and SEQ ID NO:549; o. SEQ ID NO:378; or SEQ ID NO:425 and SEQ ID NO:426; p. SEQ ID NO:379; or SEQ ID NO:421 and SEQ ID NO:437; or q. SEQ ID NO:380; or SEQ ID NO:423 and SEQ ID NO:427 The multispecific antibody according to any one of claims 1 to 11, comprising: Claim 13: a. SEQ ID NO:389; or SEQ ID NO:414 and SEQ ID NO:432; b. SEQ ID NO:400; or SEQ ID NO:414 and SEQ ID NO:436; c. SEQ ID NO:516; or SEQ ID NO:414 and SEQ ID NO:518; d. SEQ ID NO:517; or SEQ ID NO:414 and SEQ ID NO:519; e. SEQ ID NO:526; or SEQ ID NO:414 and SEQ ID NO:528; f. SEQ ID NO:527; or SEQ ID NO:414 and SEQ ID NO:529; g. SEQ ID NO:504; or SEQ ID NO:414 and SEQ ID NO:506; or h. SEQ ID NO:505; or SEQ ID NO:414 and SEQ ID NO:507; The multispecific antibody of claim 12, comprising:

14. a. SEQ ID NO:385 or SEQ ID NO:386; b. SEQ ID NO:378; or SEQ ID NO:425 and SEQ ID NO:426; c. SEQ ID NO:379; or SEQ ID NO:421 and SEQ ID NO:437; or d. SEQ ID NO:380; or SEQ ID NO:423 and SEQ ID NO:427 The multispecific antibody of any one of claims 1 to 13, which does not comprise

15. The multispecific antibody, a) a binding affinity (e.g., as measured by surface plasmon resonance, K Ｄ ) binds to human EGFR; b) specifically binds to the human variable δ1 (Vδ1) chain of the γδ T-cell receptor (TCR) with a K of less than about 10 nM, and optionally said anti-Vδ1 antibody or antigen-binding fragment thereof binds to the cyno variable δ1 (Vδ1) chain of the γδ T-cell receptor (TCR) with a K of less than about 100 nM; and / or c) causes depletion of less than about 30%, or less than about 20%, or less than about 10% of the viable V51 T+ cell population via ADCC and / or CDC; A multispecific antibody according to any one of claims 1 to 14.

16. The Fab region is a. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 68, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 95, respectively; b. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 55, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 82, respectively; c. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 56, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 83, respectively; d. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 57, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 84, respectively; e. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 58, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 85, respectively; f. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 59, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 86, respectively; g. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 60, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 87, respectively; h. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 52, 53, and 61, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 88, respectively; i. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 62, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 89, respectively; j. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 63, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 90, respectively; k. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 64, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 91, respectively; l. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 65, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 92, respectively; m. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 52, 53, and 66, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 93, respectively; n. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 67, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 94, respectively; o. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 69, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 96, respectively; p. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 70, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 97, respectively; q. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 71, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 98, respectively; r. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 72, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 99, respectively; s. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 73, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 100, respectively; t. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 52, 53, and 74, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 101, respectively; VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 75, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 102, respectively; v. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 76, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 103, respectively; w. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 77, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 104, respectively; x. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 51, 53, and 78, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 79, 80, and 105, respectively; y. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 133, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 147, respectively; z. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 134, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 148, respectively; aa. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 135, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 149, respectively; bb. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 136, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 150, respectively; cc. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 137, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 151, respectively; dd. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 138, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 152, respectively; VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 139, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 153, respectively; ff. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 140, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 154, respectively; VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 141, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 155, respectively; hh. VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 142, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 156, respectively; or ii. The multispecific antibody of any of claims 1 to 15, comprising VHCDR1, VHCDR2, and VHCDR3 comprising the amino acid sequences of SEQ ID NOs: 130, 131, and 143, respectively, and VLCDR1, VLCDR2, and VLCDR3 comprising the amino acid sequences of SEQ ID NOs: 144, 145, and 157, respectively.

17. The Fab region is a. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 15, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 40; b. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:2, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:27; c. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:3, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:28; d. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:4, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:29; e. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:5, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:30; f. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:6, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:31; g. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:7, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:32; h. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:8, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:33; i. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:9, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:34; j. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 10, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 35; k. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 11, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 36; l. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 12, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 37; m. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 13, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 38; n. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 14, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 39; o. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 16, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 41; p. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 17, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 42; q. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 18, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 43; r. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 19, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 44; s. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 20, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 45; a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 21, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 46; a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:22, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:47; v. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:23, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:48; w. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:24, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:49; x. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:25, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:50; y. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 107, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 119; z. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 108, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 120; aa. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 109, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 121; bb. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 110, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 122; cc. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 111, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 123; dd. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 112, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 124; a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 113, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 125; ff. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 114, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 126; a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 115, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 127; hh. a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 116, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 128; or ii. The multispecific antibody of any of claims 1 to 16, comprising a VH comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 117, and a VL comprising an amino acid sequence having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:

129.

18. 18. The multispecific antibody according to any of claims 1 to 17, wherein said Fab region comprises an amino acid residue other than serine at position 74 according to the IMGT numbering system, optionally wherein said residue at position 74 according to the IMGT numbering system is a leucine residue.

19. The Fab region is a. GDSVSSKSX １ A (SEQ ID NO: 158); b. a HCDR2 sequence comprising the sequence of SEQ ID NO:53; C. X ２ WX ３ X ４ X ５ X ６ D.X. ７ HCDR3 sequence comprising the sequence of (SEQ ID NO: 162), wherein said HCDR3 sequence is not SEQ ID NO: 54; d. an LCDR1 sequence comprising the sequence of SEQ ID NO:79; e. a LCDR2 sequence comprising the sequence of SEQ ID NO: 80; and f. QQX ８ YX ９ X １０ X １１ X １２ X １３ T (SEQ ID NO: 166), wherein said LCDR3 sequence is not SEQ ID NO: 81; X １ ~X １３ each of which is a naturally occurring amino acid, or or the antibody or antigen-binding fragment thereof, a. a HCDR1 sequence comprising the sequence of SEQ ID NO: 130; b. a HCDR2 sequence comprising the sequence of SEQ ID NO: 131; C. X １ X ２ YX ３ X ４ an HCDR3 sequence comprising the sequence of AFDI, wherein said HCDR3 sequence is not SEQ ID NO: 132; d. an LCDR1 sequence comprising the sequence of SEQ ID NO: 144; e. a LCDR2 sequence comprising the sequence of SEQ ID NO: 145; and f. QQX ５ X ６ X ７ X ８ LX ９ T, wherein said LCDR3 sequence is not SEQ ID NO: 146; X １ ~X ９ A multispecific antibody according to any one of claims 1 to 18, wherein each of is a naturally occurring amino acid.

20. The Fab region is a) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 562; b) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 522; c) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 532; d) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 541; e) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 510; f) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 559; or g) A multispecific antibody according to any of claims 1 to 19, comprising a VH sequence comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO:

552.

21. The Fab region, a) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 562; b) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 522; c) a VH comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO: 532; or d) A multispecific antibody according to claim 20, comprising a VH sequence comprising the amino acid sequence of SEQ ID NO: 15 and a VL sequence comprising the amino acid sequence of SEQ ID NO: 40, wherein the Fc region comprises a CH3 domain comprising the amino acid sequence of SEQ ID NO:

510.

22. a. A binding affinity (e.g., as measured by surface plasmon resonance, K Ｄ ) binds to human TRDV1 (SEQ ID NO: 272 or 306); b. Optionally, a binding affinity (e.g., as measured by surface plasmon resonance, K Ｄ ) binds to cynomolgus TRDV1 (SEQ ID NO: 308); c. A multispecific antibody according to any of claims 1 to 21, having an IC50 for TCR down-modulation of less than about 50 nM (preferably less than about 10 nM).

23. 23. The multispecific antibody according to any of claims 1 to 22, wherein the Fab region binds only to an epitope within amino acid residues 1 to 90 of SEQ ID NO:272, SEQ ID NO:306 and / or SEQ ID NO:

308.

24. The Fab region is (i) amino acids 3 to 20 of SEQ ID NO:272, SEQ ID NO:306, and / or SEQ ID NO:308; and / or (ii) A multispecific antibody according to any of claims 1 to 23, which binds to an epitope within the region of amino acids 37 to 77 of SEQ ID NO: 272, SEQ ID NO: 306, and / or SEQ ID NO:

308.

25. the Fab region binds to an activation epitope of a γδ T cell, and optionally binding of the activation epitope (i) downregulates the γδ TCR, (ii) activates degranulation of the γδ T cell, and / or (iii) promotes killing by the γδ T cell; and / or The multispecific antibody of any one of claims 1 to 24, wherein binding of the activating epitope upregulates expression of CD107a, CD25, CD69 and / or Ki67.

26. The multispecific antibody of any one of claims 1 to 25, wherein the multispecific antibody is a bispecific antibody.

27. The multispecific antibody of any one of claims 1 to 26, wherein the multispecific antibody is not a bispecific antibody.

28. A pharmaceutical composition comprising the multispecific antibody as defined in any one of claims 1 to 27 and a pharma- ceutically acceptable diluent or carrier.

29. A pharmaceutical composition comprising a multispecific antibody according to any one of claims 1 to 27, or the pharmaceutical composition according to claim 28, for use in treating a disease or disorder in a subject or in modulating an immune response in a subject.

30. Optionally, the disease or disorder is cancer or the subject in which the immune response is modulated has cancer.

30. The pharmaceutical composition of claim 29, wherein the cancer is an EGFR positive cancer.

31. 30. The pharmaceutical composition of claim 29, wherein modulating the immune response in the subject comprises at least one selected from the group consisting of activating γδ T cells, causing or increasing proliferation of γδ T cells, causing or increasing expansion of γδ T cells, causing or increasing degranulation of γδ T cells, causing or increasing killing activity by γδ T cells, causing or increasing γδ T cytotoxicity, causing or increasing recruitment of γδ T cells, increasing survival rate of γδ T cells, and increasing resistance to exhaustion of γδ T cells.

32. The pharmaceutical composition of any one of claims 29 to 31, wherein diseased cells are killed and healthy cells are spared.

33. A pharmaceutical composition comprising a multispecific antibody according to any one of claims 1 to 27, or the pharmaceutical composition according to claim 28, for use in the treatment of cancer.