Antibody conjugated chemical inducers of degradation of RBM39 and therapeutic uses thereof

Abstract

The present invention relates to immunoconjugates comprising: a) an antibody binding moiety that binds to and / or targets a tumor antigen and / or a cancer antigen, whereby said tumor antigen and / or said cancer antigen is preferably displayed on the surface of a tumor cell and / or a cancer cell; and whereby said antibody binding moiety is preferably an antibody, an antibody fragment or an antibody construct that preferably binds to / targets the in tumor / cancer antigen GD2; and b) a compound according to formula (I) which is and / or which functions preferably as an RBM39 degrader. The instant immunoconjugates are particularly useful in treatment or prevention of tumors or cancers characterized by increased expression of RBM39, in particular tumors and cancers also characterized by increased expression of GD2 or presence of the GD2 antigen on the cell surface.

Description

[0001] Antibody Conjugated Chemical Inducers Of Degradation Of RBM39 And

[0002] Therapeutic Uses Thereof

[0003] Field of the invention

[0004] The present invention relates to immunoconjugates comprising a) an antibody / antibody fragment / antibody construct / binding moiety binding to / targeting a tumor antigen or a cancer antigen that is preferably displayed and / or expressed on the surface of a tumor and / or cancer cell; and b) a compound according to formula (I) as provided below.

[0005] The inventive immunoconjugate(s) can comprise, in particular, a) an antibody, antibody fragment / antibody construct and / or a binding moiety that binds / targets GD2 (a disialoganglioside tumor-associated antigen); and b) a compound according to formula (I) which is capable of inducing degradation of the oncoprotein RBM39 (herein “RBM39 degrader”).

[0006] Accordingly, the present invention provides for immunoconjugates that comprise: a) an antibody binding moiety to a tumor antigen and / or a cancer antigen, whereby said tumor antigen and / or a cancer antigen is preferably displayed on the surface of a tumor cell and / or of a cancer cell and whereby said antibody binding moiety is preferably an antibody, an antibody fragment or an antibody construct that preferably binds to the tumor / cancer antigen GD2; and b) a compound according to formula (I):

[0007]

[0008] The compound of formula (I) is and / or functions, preferably, as an “RBM39 degrader”.

[0009] The immunoconjugates of the present invention are particularly useful in treatmentor prevention of tumors or cancers. Preferably, these tumors or cancers are characterized by increased expression of RBM39. These tumors and cancers may also show an increased expression of GD2 and / or the presence of the GD2 antigen on their cell surface.

[0010] Accordingly, the inventive immunoconjugates as provided herein are particularly useful in treatment or prevention of tumors / cancerthat are characterized by expression of the oncoprotein RBM39 and / or by an increased expression of RBM39. Cancers / tumors that are characterized by an increased expression of GD2 and / or the presence of GD2 antigen on the cell surface can also be treated by the immunoconjugates of the invention.

[0011] Background of the invention

[0012] Induction of targeted protein degradation (TPD) has recently emerged as a new therapeutic strategy that has expanded the druggable proteome for cancer treatment. TPD involves the use of small molecule degraders which hijack the endogenous ubiquitin-proteosome pathway and selectively induce degradation of a target protein of interest (POI). Unlike classic occupancy-based drugs, TPD eliminates the target and works catalytically, and so can be more efficacious and sustained, with potentially lower dose requirements.

[0013] Increasing amount of evidence shows that the pre-mRNA splicing factor RNA-binding motif protein 39 (RBM39) is overexpressed / upregulated in several types of cancer (increased expression of RBM39). RBM39 is as a proto-oncogene involved the tumor / cancer development and progression via regulation of tumor-related gene expression, alternative pre-mRNA splicing and protein translation.1These tumors / cancers are characterized herein as tumors / cancers that express RBM39 (expression of the oncoprotein RBM39).

[0014] Expression of RBM39 is upregulated in a panel of adult and pediatric malignancies and it has been shown that the loss of RBM39 disrupts spliceosome and induces significant genome-wide splicing errors which are lethal to several types of cancers, including neuroblastoma, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, melanoma, leukemias, like acute myeloid leukemia (AML) or B-cell acute lymphoblastic leukemia (B-ALL), breast cancer, lung cancer, ovarian cancer or colorectal cancer.1

[0015] Therefore, RBM39 has emerged as a potential therapeutic target for cancer treatment.1However, its pharmacological targeting had been challenging until the recent discovery of a class of anti-cancer aryl sulfonamides such as indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS) and tasisulam (LY-573636) which act as molecular glue degraders and selectively induce proteasomal degradation of RBM39 via recruitment of the DCAF15 E3 ubiquitin ligase, leading to cancer cell death and tumor regression.2-3

[0016] Importantly, pre-mRNA splicing has been reported as a potential therapeutic vulnerability in MYC-driven cancers, such as MYC-driven high-risk neuroblastoma. Neuroblastoma is the most common extracranial childhood solid tumor characterized by one of the lowest survival rates among all pediatric malignancies. Amplification of the MYCN oncogene is present in about 25% of all neuroblastomas (-40% of high-risk neuroblastomas cases) and is an extremely adverse prognostic factor with -50% five-year overall survival rate.

[0017] The exceptional sensitivity towards targeted protein degradation (TPD) of RBM39 is the result of the combination of the dependency on RBM39-mediated RNA splicing and overexpression of the DCAF15, making RBM39 degradation a promising therapeutic strategy for high-risk neuroblastoma. Subsequently, the efficacy of some RBM39 small molecule degraders was successfully validated in in vitro and in vivo preclinical models of high-risk neuroblastoma.4-6

[0018] Furthermore, high-risk neuroblastoma was the first pediatric cancer that received authorization for the clinical use of immunotherapy. The target of the antibody-based immunotherapy is GD2, a disialoganglioside tumor-associated antigen (TAA), that is present in high density on the surface of most of neuroblastoma tumor cells. Incorporation of anti-GD2 therapeutic antibodies, administered either alone or in combination with immunostimulatory agents, into standard of care treatment protocols has significantly improved survival rates of high-risk neuroblastoma patients.6However, about 40% patients still do not respond or relapse after the treatment6"6indicating that some of the neuroblastoma tumor cells might be able to escape anti-G D2 therapy. This suggests that the efficacy of the anti-G D2 antibody-based immunotherapy needs to be improved so that more patients, for example patients suffering from neuroblastoma, in particular patients with high-risk neuroblastoma (including those with refractory or relapsed disease) can benefit from this treatment approach.

[0019] Various GD2-directed therapeutic approaches, e.g., chimeric antigen receptor (CAR) T, CAR-natural killer (NK) T cells or bispecific trifunctional antibodies (trAb) have been developed and underwent either preclinical or clinical testing. Anti-GD2 CAR T cells for the treatment of relapsed or refractory high-risk neuroblastoma were tested in a phase 1-2 academic trial (NCT03373097)9but no significant increase in the 3-year overall survival rate (60%) or event-free survival rate (36%) was observed in comparison to the long-term, continuous single-agent dinutuximab beta therapy (NCT02743429)10(66% and 31%, respectively). Furthermore, in this anti-GD2 CAR T cells approach, a not negligible side-effect, namely cytokine release syndrome, occurred in 74% patients. CAR-NKT cells were also tested in a phase 1 trial for relapsed or refractory high-risk neuroblastoma (NCT03294954)11and 25% objective response rate was observed with this type of therapy which is comparable to the dinutuximab beta antibody (26%) therapy but lower compared to objective responses observed with anti-GD2 CAR T cell (63%) therapy. Recently, anti-GD2 / anti-CD3 bispecific trifunctional antibodies (trAbs) have demonstrated reduction or complete elimination of neuroblastoma metastases in a syngeneic mouse model with superior anti-tumor activity compared to dinutuximab beta antibody.12However, efficacy of such tri-functional antibodies has not yet been evaluated in neuroblastoma in human patients or in close-to-human models, reflecting the clinical situation in human patients.

[0020] One strategy to increase the efficacy of the antibody-based immunotherapy is through their chemical modification with small molecule cytotoxic drugs in a concept known as immunoconjugates or, in other words, antibody-drug conjugates (ADCs). Accordingly, ADCs have emerged as an effective anti-cancer biological drug class that combines the benefits of highly specific targeting ability and potent cytotoxic effect to achieve accurate and efficient killing of cancer cells. The therapeutic concept of ADCs uses an antibody, such as monoclonal antibody as a vehicle targeting a tumor-associated or -specific antigen to deliver highly potent (cytotoxic) payload selectively to the tumor cells, thus enhancing the therapeutic index and minimizing the unwanted side effect of anti-cancer agents. In addition, ADCs can also interact with both cancer and immune cells by eliciting mechanisms such as immunogenic cell death or antibodydependent cell-mediated cytotoxicity (ADCC), ultimately providing potential synergism with immunotherapy which further increase the treatment efficacy. Importantly, ADC biotherapeutic platform has already shown proof-of-concept therapeutic potential for the treatment of various types of cancers with about half of the ADCs being currently clinically approved for the treatment of solid tumors.

[0021] Despite the recent addition of the anti-GD2 antibody-based immunotherapy13to the standard of care for high-risk neuroblastoma and the strong clinical potential of ADCs which have demonstrated substantial improvement over available therapies and unmet medical needs for the treatment of solid tumors, the anti-GD2 ADC biotherapeutic platform remains surprisingly underexplored, especially in the context of high-risk neuroblastoma therapy.14'15ADCs targeting different surface markers on neuroblastoma cells, e.g., ALK,16GPC2,17-19B7-H320have been developed and in vivo preclinical studies provided rationale for their clinical development. However, therapeutic efficacy or potential side effects of any of these ADC constructs have so far not been evaluated in high-risk neuroblastoma clinical trials, pointing towards the need and space for new, more potent and safer strategies for targeting neuroblastoma tumors.

[0022] WO 2023 / 172968 discloses certain anti-GD2 antibody-based conjugates. WO 2023 / 172968 refers to ‘M3554’ (therein “molecule 1”), that links exatecan, a DNA topoisomerase I inhibitor payload, with a humanized (hu14.18 K322A lgG1 .4 with reduced FcyR binding) anti-GD2 antibody via p-glucuronidase- cleavable linker. The purpose of the Fc-region antibody modification is to abrogate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) which are associated with side effects of the antibody-based anti-GD2 immunotherapy. This ADC has entered its first-in-human study (NCT06641908). M3554 is evaluated in patients with solid tumors with high GD2 prevalence, such as neuroblastoma, where GD2 has been validated as a target for naked antibody therapy, as well as soft tissue sarcoma, glioblastoma, and osteosarcoma. However, exatecan is a highly cytotoxic payload that can also affect healthy cells and cause adverse effects (as also illustrated in appended, comparative examples).

[0023] One of the limitations that is hindering the translation of the anti-GD2 ADC into the clinical development is indeed the use of highly cytotoxic anti-cancer drug payloads, e.g., tubulin inhibitors, DNA damaging agents or DNA topoisomerase I inhibitors (see, e.g. exatecan as discussed, supra). Premature ADC payload release in the extratumoral compartments, non-specific endocytosis of the intact ADC, off-target receptor-mediated uptake of ADCs or on-target off-tumor toxicities due to the expression of the ADC target antigens in healthy tissue may lead to unacceptable toxicity profiles and premature termination of the clinical development of such ADC constructs. As an example, a higher incidence of peripheral neuropathy has been reported in ADCs containing monomethyl auristatin E (MMAE)21which is a cytotoxic drug payload frequently used in the development of ADC biotherapeutics. A solution to avoid such unwanted and life-threatening toxicities could be the utilization of payloads anti-cancer activity and efficacy of which (unlike the above-mentioned inhibitors) does not solely depend on the expression and activity of the target POI, but also on a range of additional proteins, including E3 ligases and associated factors. Such requirements are fulfilled by molecular glue degraders which enable efficient tissue-specific removal of disease-causing proteins with decreased risk of off-target toxicity compared to conventional inhibitor drugs.

[0024] As it is the case for conventional cytotoxic ADC payloads, the cancer cell specificity, efficacy and safety profile of molecular glue degrader payloads can be potentially improved through the precise delivery to cancer cells using antibodies targeting tumor-associated antigens (TAAs). It is hoped for in the art that targeted protein degradation in combination with antibody-mediated delivery technology may overcome the limitations of each of these modalities. However, therapeutic success is not always a given.

[0025] It has been suggested that ‘RBM39’ plays an important role in cancer immunity.22RBM39 expression could be associated with the less permissive tumor microenvironment and lower immune cell infiltration. In addition, it has also been shown that pharmacologic modulation of splicing via aryl sulfonamide RBM39 molecular glue degraders lead to the generation of novel neoantigens presented on tumor MHC class I and enhanced anti-tumor immunity.23

[0026] However, there are a range of unwanted side effects expected in the art for anti-GD2 antibody therapy as well as in the use of RBM39 degraders. These undesired side effects are, inter alia, associated with, e.g., (but not only) allodynia, neuropathy and acute neuropathic pain. These unwanted / undesired side effects have been described especially in context of anti-GD2 monoclonal antibody (mAb) infusions. These issues limit the dosage and efficacy of the anti-GD2 immunotherapy for high-risk neuroblastoma. Furthermore, based on the collated results from Phase I and II clinical trials, the most common side effects reported for RBM39 degraders E7820 and indisulam (E7070) include fatigue, constipation, diarrhea, nausea, anemia, neutropenia and thrombocytopenia. Accordingly, there is a need for novel therapeutic approaches devoid of, or at least minimizing, these side effects.

[0027] Summary of the invention

[0028] Particularly desirable are cancer therapies with high efficacy, at the same time causing limited side effects. It is further desirable to be able to target immunologically “cold” tumors, such as pediatric malignancies, including pediatric neuroblastoma. Accordingly, it is desirable to provide efficient means and methods that are capable of successfully targeting tumors / cancers medically. These means and methods should also avoid and / or at least minimize adverse and unwanted side effects.

[0029] Thus, it is a technical problem of the present invention to provide an improved therapy against cancer, in particular neuroblastoma, such as pediatric neuroblastoma.

[0030] The problem is solved by the embodiments provided herein and as characterized by the claims. The inventive means and methods provided herein surprisingly fulfill medical requirements of a desired high efficacy with considerably reduced or limited side effects in the medical intervention of tumors / in cancer. Furthermore, even immunologically inert, i.e. “cold" tumors can surprisingly to be targeted by the herein provided immunoconjugates.

[0031] The present invention provides for immunoconjugates comprising: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen (herein also “moiety (a)”); and b) a compound according to formula (I) as shown herein below (herein also “moiety (b)”.

[0032] In particular, the herein provided immunoconjugates are therapeutically useful when said tumor antigen and / or to a cancer antigen to be bound and / or to be targeted by said antibody, antibody construct, and / or binding moiety is expressed and / or displayed on the surface of a tumor and / or cancer cell.

[0033] Accordingly, herein provided are in particular immunoconjugates that comprise: a) an antibody, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen displayed on the surface of a tumor and / or cancer cell (herein also “moiety (a)”); and b) a compound according to formula (I) as shown herein below (herein also “moiety (b)”. Said “moiety (a)” of the immunoconjugates of the present invention binds to (and / or targets) tumor- associated antigens (TAAs) and / or cancer-associated antigens (CAAs). Herein disclosed and exemplified are such tumor antigens and / or such cancer antigens that are, preferably, expressed and / or displayed on the surface of a tumor and / or cancer cell. Corresponding examples of such antigens are, inter alia, provided in Table 1, infra.

[0034] In accordance with the present invention, the compound according to formula (I) as comprised in “moiety (b)” of the herein provided immunoconjugates is or can function as a degrader of the RBM39 oncoprotein. RBM39 refers to the pre-mRNA splicing factor RNA-binding motif protein 39 (RBM39). This protein is known to the skilled person. For example, its protein sequence can be retrieved in the UniProt database under UniProt code Q14498. This protein is an RNA binding protein and a splicing factor. The RBM39 protein is found in the nucleus where it colocalizes with core spliceosomal proteins.

[0035] The present invention provides antibody-drug conjugates (herein ‘immunoconjugates’) of surprisingly increased potency, efficacy and safety of both targeted protein degradation of oncoprotein RBM39 and antibody-based immunotherapy through the precise antibody-mediated cancer cell-specific delivery of small molecule glue degraders of RBM39 RNA splicing factor in the form of RBM39 (the herein disclosed inventive immunoconjugates are also termed “degrader-antibody conjugates" or DACs”). The surprising advantages of the present invention are in particular illustrated herein by an inventive immunoconjugate that combines anti-GD2 immunotherapy and targeted protein degradation of oncoprotein RBM39 with unexpected and surprising results.

[0036] Whereas molecular glue degraders are typically small molecules that indiscriminately enter both healthy and diseased cells throughout the body, attachment of the degrader payloads to antibodies drives localization to specific sites and cells. In the form of immunoconjugates involving a degrader, or in other words degrader-antibody conjugates (DACs), such a biotherapeutic approach results in increased potency, improved pharmacokinetic and pharmacodynamic profiles and potentially reduced likelihood of systemic exposure and toxicity of small molecule degrader drugs.

[0037] In context of the present invention, it was surprisingly found and demonstrated that combining a (anti- GD2) mAb targeting a TAA (present, e.g., in high copy numbers on the surface of cancer cells) with a non-neurotoxic molecular glue degrader payload that targets an oncoprotein in an immunoconjugate format, selectively delivers a cytotoxic, yet not non-neurotoxic, payload to malignant cells (to kill / eliminate them) without triggering unwanted toxicities.

[0038] As shown herein, the exemplified oncoprotein to be targeted by said molecular glue degrader payload is RBM39. RBM39 is overexpressed in cancer cells, such as neuroblastoma cells and expressed only in low levels in the healthy tissue. RBM39 is required for the growth and survival of these cancer cells. Moreover, the anti-cancer activity of the specific molecular glue degrader targeting RBM39, as provided in formula (I) herein below, may also dependent on an E3 ligase DCAF15 that is also overexpressed in these particular cancer cells (and has only low expression in the healthy tissue). In context of the present invention, it could surprisingly be shown that the exemplified means and methods as provided herein, and in particular the provided novel and inventive immunoconjugates (like, e.g., the anti-GD2 / RBM39 degrader-antibody conjugates / immunoconjugates of the invention) can avoid and / or relevantly reduce undesired side-effects, like, e.g., peripheral neuropathies, as well as hematological toxicities. Undesired / unwanted side effects, as documented in the art by antibody therapy are indeed dose limiting and can hamper therapeutic efficacy of the antibody therapy. The immunoconjugates of the present invention successfully overcome these hurdles.

[0039] The invention is also summarized in the following embodiments.

[0040] The present invention relates to immunoconjugates comprising: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen; and b) a compound according to formula (I) as shown herein below.

[0041] The present invention, provides for immunoconjugates comprising: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a tumor cell and / or cancer cell (herein also “moiety (a)”); and b) a compound according to formula (I) as shown herein below (herein also “moiety (b)”).

[0042] In particular, the herein provided immunoconjugates are therapeutically useful when said tumor antigen and / or to a cancer antigen to be bound and / or to be targeted by said antibody, antibody construct, and / or binding moiety is expressed and / or displayed on the surface of a tumor cell and / or cancer cell. Accordingly, herein provided are in particular immunoconjugates that comprise: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen that is preferably displayed on the surface of a tumor cell and / or cancer cell (herein also "moiety (a)"); and b) a compound according to formula (I) as shown herein below (herein also “moiety (b)”).

[0043] In particular, provided herein are immunoconjugates that comprise: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen that is displayed on the surface of a tumor and / or cancer cell (herein also “moiety (a)"); and b) a compound according to formula (I) as shown herein below (herein also “moiety (b)”).

[0044] Accordingly, in one embodiment, the present invention relates to (an) immunoconjugate(s) comprising: a) an antibody, an antibody fragment, antibody construct and / or a binding moiety binding to a tumor antigen and / or to a cancer antigen displayed on the surface of a tumor cell and / or cancer cell; and b) a compound according to formula wherein

[0045] R1is selected from -H, C1.5 alkyl, -OH, -CN and -NO2;

[0046] R2is selected from -H, halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -CN, -NO2, -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and - SO2N(C1-5 alkyl)(C1-5 alkyl);

[0047] R3is selected from -H, halogen, C1.5 alkyl, aryl, -OH, -0(C1-5 alkyl), -CN, -NO2, -NH2, -NH(C1-5 alkyl), - N(CI-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(Ci.

[0048] 5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);

[0049] R4is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, - SO2NH(Ci.5alkyl) and -SO2N(CI-5 alkyl)(C1-5 alkyl); R5is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONHfCu alkyl), -CON(Ci.salkyl)(C1-5 alkyl), -SO2NH2, - SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);

[0050] A is a phenyl or five- or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs; and each Rsis independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -O(C1-5 alkyl), -(C1-5 alkylene)-OH, -CN, -NH2, -(C1-5 alkylene)-NH2, -(C1.5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)-N(Ci-s alkyl)(C1-5 alkyl), -O-(C1-5 alkylene)-NH2, -O-(C2-5 alkylene)-NH(C1-5 alkyl), -O-(C2-5 alkylene)-N(C1-5 alky l)(C 1-5 alkyl), -NO2, -NH(C1-5 alkyl), -N (C 1-5 alkyl)(Ci.5alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(CI-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(CI-5 alkyl) and -SO2N(CI-5 alkyl)(C1-5 alkyl).

[0051] In context of this invention, it was surprisingly found that immunoconjugates targeting via their "moiety (a)”, (for example via an antibody, an antibody fragment, an antibody fragments, an antibody construct and / or a binding moiety) tumor and / or cancer antigen(s) on tumor / cancer cells), are of particular and unexpected high potency when the immunoconjugates comprise as “moiety (b)” the compound according to formula (I). Said "moiety (b)” is also considered as the “payload” in the immunoconjugates in context of this invention. As illustrated herein, “moiety (b)” of the inventive immunoconjugates can function as (a) degrader(s) of the RBM39 oncoprotein.

[0052] As illustrated herein, the targeting “moiety (a)” of inventive immunoconjugate(s), i.e. the moiety that binds to a tumor antigen and / or cancer antigen displayed on the surface of a cancer cell, can be an antibody, an antibody construct or another binding moiety that selectively targets and / or binds to said tumor and / or cancer antigen. Examples of such antibodies provided herein and illustrated in the appended technical part. For example, the present invention is illustrated by anti-GD2 antibodies as “moiety (a)” if the inventive immunoconjugates that comprise as “moiety (b)” the compound according to formula (I) / the compound of formula (I). Besides full-length targeting antibodies for “moiety (a)”, provided herein below are further useful examples of moieties that can serve as “moiety (a)”. These comprise, inter alia, antibody construct like antibody fragments or antibody constructs. The “moiety (a)” of inventive immunoconjugate(s) has activity / the ability of binding to and / or targeting of a tumor antigen and / or to a cancer antigen displayed / expressed on the surface of a cancer cell. This also applies when antibody fragments or antibody constructs are applied as “moiety a”. Binding moieties that are not considered antibodies, antibody fragments or antibody constructs and that selectively target and / or bind tumor and / or cancer antigens are known in the art. Such binding moieties may comprise but are not limited to, e.g., peptides, aptamers, small binding molecules (e.g. vitamins such as folic acid), antibody / aptamer-coated nanoparticles, etc.. Yet, as also illustrated herein below, in context of the present invention, “moiety (a)” of the inventive immunoconjugates comprises in a preferred embodiment an antibody, an antibody fragment and / or an antibody construct directed against a tumor antigen and / or to a cancer antigen. A preferred embodiment in this context is an antibody (a full-length antibody) that targets the antigens. Preferably, the tumor and / or cancer antigen(s) to be targeted also in an in vivo setting are displayed on the surface of a cancer cell.

[0053] The present invention also relates to a pharmaceutical composition comprising the herein described inventive immunoconjugate(s). These pharmaceutical compositions may also comprise a carrier, like a pharmaceutically acceptable carrier.

[0054] The present invention further relates to (an) immunoconjugate(s) of the present invention or a pharmaceutical composition of the present invention for use as a medicament.

[0055] The immunoconjugate(s) of the present invention or a pharmaceutical composition of the present invention may be used in the in treatment or prevention of cancer.

[0056] The present invention also provides for use of the inventive immunoconjugate(s) as described herein in manufacture of a medicament for the treatment or prevention of a tumor and / or of cancer.

[0057] The present invention also relates to a method of treatment of cancer that comprises administering an immunoconjugate of the present invention to an individual in need thereof. This individual may be a mammal and, in one embodiment, said individual is a human, in particular a human patient in need of medical intervention. The individual is, in one embodiment, an human patient suffering or prone to suffer from cancer / a tumor. In such medical intervention, a therapeutically effective dose of the inventive immunoconjugate(s) is to be administered.

[0058] The present invention relates further to a compound of formula:

[0059] ZZ-U-LP-L2-X-Y

[0060] (III) or a pharmaceutically acceptable salt thereof, wherein Zz is Zi or Z2

[0061] Z1 is selected from selected from , tly is Hal

[0062] (such as Cl, Br or I) or -S-aryl (such as -S-phenyl), wherein Rxis C1-5 alkyl

[0063] (such as methyl or ethyl), C2-5 alkenyl or C2-5 alkynyl (such as propargyl);

[0064] Li, LP, L2, and X are as defined for formula (II); and Y is the moiety of formula (la), or the moiety of formula (lb).

[0065] Also, inventive immunoconjugates comprising these compounds of formula Zz-Li-Lp-1_2-X-Y can be of medical use as described herein and may also be employed in medical interventions, like in the treatment or the prevention of cancers / tumors, Brief description of figures

[0066] The invention is illustrated with the following and appended figures. The figures are not to be construed as limiting the scope of the invention in any way, which is defined by the hereto appended claims and in the herein described embodiments.

[0067] Fig. 1 shows schematic illustration of E7820 compound and its interactions with DCAF15 and RBM39, highlighting the key amino acid residues and functional groups important for the biological activity of E7820 compound. Figure copied from reference25.

[0068] Fig. 2 shows indisulam-mediated interactions between DCAF15 and RBM39. Indisulam compound bridges the structure of DCAF15 and RBM39 by forming several direct or water-mediated interactions with both DCAF15 and RBM39 leading to increased complementarity between the two surfaces. Hydrogen bonds are shown as doted lines and the surfaces of both DCAF15 and RBM39 are shown with key residues labeled. Figure copied from reference26.

[0069] Fig. 3 presents dinutuximab beta antibody (i.e. , an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16) internalization rates plotted against cell surface present GD2 assessed by flow cytometry on a test panel of human neuroblastoma cell lines. Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown.

[0070] Fig. 4 shows the results of the cell viability-based degrader payload screen evaluated by CellTiter- Blue® cell viability assay after 72 h treatment and plotted as ECso values. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted and ECso values were calculated using log(inhibitor) vs. response -- variable slope equation in GraphPad Prism 9 software. This experiment was performed once, in technical triplicates and results were validated in the follow-up experiments. RBM39 molecular glue degrader E7820 displayed <150 nM anticancer activities in 7 out of 10 tested neuroblastoma cell lines, 5 of which bear MYCN oncogene amplification. Fig. 5 presents structure of the maleimide-containing chemical modifier (compound id: JKW-68) with AMe-deCN-E7820 (compound id: JKW-48) as the RBM39 degrader payload used for the preparation of the first generation anti-GD2 / RBM39 DACs (drug-to-antibody ratio (DAR) 4-8).

[0071] Fig. 6 shows schematic illustration of the preparation of anti-GD2 DACs comprising of a controlled interchain disulfide reduction using tris(2-carboxyethyl)phosphine (TCEP) followed by a sitespecific modification of the reduced Cys thiol groups using maleimide-containing chemical linkers. Reaction conditions such as temperature, reaction time, reaction buffer, amount of the TCEP reagent and finally amount of the maleimide-containing chemical modifier were optimized to obtain DACs with average DAR ranging from 4 to 8.

[0072] Fig. 7 presents data on in vitro anti-cancer activity of the first generation anti-GD2 / RBM39 DACs in (a) IMR-32 (GD2+) and (b) SK-N-SH (GD2j neuroblastoma cell line evaluated by CellTiter-Blue® cell viability assay after 72 h treatment. DAC1 corresponds to an anti-GD2 / RBM39 DAC with an average DAR ~4 whilst DAC2 to an anti-GD2 / RBM39 DAC with an average DAR -6. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted. Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown. ECso values were calculated using log(inhibitor) vs. response -- variable slope equation in GraphPad Prism 9 software. Both conjugates are illustratively based on dinutuximab beta antibody (i.e., an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16).

[0073] Fig. 8 shows surface GD2 expression in the selected neuroblastoma cell lines used in the anti- GD2 / RBM39 DAC in vitro biological activity evaluation experiments assessed by flow cytometry. Results show that IMR-32 cells contain -2.5 times higher number of surface GD2 disialoganglioside TAA compared to STA-NB-1 .2 cells, whereas only low amount of GD2 can be detected on the surface of SK-N-SH cells. Viable neuroblastoma cells were selected using a FACS gating strategy comprising of FSC-A / SSC-A selection of neuroblastoma cells, FSC-A / FSC- H exclusion of doublets and finally selection of FSC-A / PI- viable neuroblastoma cells. Geometric mean fluorescence intensity was determined for every sample, BD Quantibrite™ Phycoerythrin (PE) Fluorescence Quantitation Kit (BD Biosciences 340495) were analyzed according to the manufacturer’s instructions with every run. This was used to generate a standard curve from which the PE geometric mean for each sample was converted into the number of antibodies bound per cell (ABC) representing surface antigen expression. Error bars represent SD. This experiment was performed three times, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown.

[0074] Fig. 9 presents in vitro anti-cancer activity of the first generation anti-GD2 / RBM39 DAC (i .e. , comprising dinutuximab beta antibody, i.e., an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16, and compound JKW-68) .or DB (dinutuximab beta) antibody in 22 h co-culture assay with freshly isolated human HD NK cells in GD2+(a) IMR-32 and (b) STA-NB-1.2 neuroblastoma cell line evaluated by flow cytometry-based assay. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls containing target viable neuroblastoma cells only were plotted. Viable neuroblastoma cells were selected using a FACS gating strategy comprising of the selection of VPD450+cells, then FSC-A / SSC-A selection of neuroblastoma cells, FSC-A / FSC-H exclusion of doublets and finally selection of VPD450V7- AAD- viable neuroblastoma cells. E:T represents effector (NK cells) to target (neuroblastoma cells) ratio. Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown.

[0075] Fig. 10 discusses proposed novel and unique mechanism of action of the anti-GD2 / RBM39 DACs leading to increased anti-cancer efficacy against neuroblastoma tumor cells.

[0076] Fig. 11 discusses in vitro anti-cancer activity of anti-GD2 / RBM39 DACs prepared using linker-modified payload JKW-162 (DAR ~8) and dinutuximab beta antibody (an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16) in (a) IMR-32 (GD2+) and (b) SK-N-SH (GD2j neuroblastoma cell line evaluated by CellTiter-Blue® cell viability assay after 72 h treatment. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted. Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown. EC50 values were calculated using log(inhibitor) vs. response -- variable slope equation in GraphPad Prism 10 software.

[0077] Fig. 12 presents in vitro anti-cancer activity of anti-GD2 / RBM39 DACs prepared using linker-modified payload JKW-162 (DAR ~8) and various antibodies as delivery vehicles (i.e., dinutuximab beta antibody, i.e., an antibody characterized by HC with a sequence according to SEQ ID NO.: 15 and LC with a sequence according to SEQ ID NO.: 16, naxitamab, i.e., an antibody characterized by HC with a sequence according to SEQ ID NO.: 17 and LC with a sequence according to SEQ ID NO.: 18; and gemtuzumab, i.e., an antibody characterized by HC with a sequence according to SEQ ID NO.: 66 and LC with a sequence according to SEQ ID ON.: 67) in (a) IMR-32 (GD2+) and (b) SK-N-SH (GD2j neuroblastoma cell line evaluated by CellTiter-Blue® cell viability assay after 72 h treatment. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted . Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown. EC50 values were calculated using log(inhibitor) vs. response - variable slope equation in GraphPad Prism 10 software.

[0078] Fig. 13 shows in vitro anti-cancer activity comparison of the anti-GD2 DAC to ADCs bearing different payloads prepared using linker-modified payloads JKW-8, JKW-130 and JKW-162 and dinutuximab beta antibody (an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16) in (a) IMR-32 (GD2+) and (b) SK-N-SH (GD2-) neuroblastoma cell line evaluated by CellTiter-Blue® cell viability assay after 72 h treatment. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted. Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown. EC50 values were calculated using log(inhibitor) vs. response -- variable slope equation in GraphPad Prism 10 software. Exatecan (employed herein as a control payload) is a highly cytotoxic payload that also affects healthy cells and may cause adverse effects. The control experiment presented in this figure documents that when exatecan is attached to an anti-GD2 antibody, it exhibits cytotoxic effect also in the GD2-negative cell line SK-N-SH. In contrast, immunoconjugate(s) of the present invention (for example the herein described anti-GD2-E7820 DAC) does not show such an undesired effect. With the inventive immunoconjugates, such undesired effects are reduced to minimum or even eliminated.

[0079] Fig. 14 shows in vitro anti-cancer activity of the anti-GD2 / RBM39 DAC prepared using compound JKW-

[0080] 162 (linker-modified E7820 MGD payload) or dinutuximab beta antibody (an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16) in 72 h co-culture assay with freshly isolated human HD NK cells in GD2+(a) IMR-32 or (b) STA-NB-1 .2 and (c) SK-N-SH (GD2 ) neuroblastoma cell line evaluated by flow cytometry. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls containing target viable neuroblastoma cells only were plotted. Viable neuroblastoma cells were selected using a FACS gating strategy comprising of the selection of VPD450+cells, then FSC-A / SSC-A selection of neuroblastoma cells, FSC-A / FSC-H exclusion of doublets and finally selection of VPD450V7- AAD- viable neuroblastoma cells. E:T represents effector (NK cells) to target (neuroblastoma cells) ratio. Error bars represent SD. Each experiment was performed at least three times, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown.

[0081] Fig. 15 presents in vitro anti-cancer activity of anti-GD2 / RBM39 DACs employing two different linker strategies for the RBM39 MGD payload attachment assessed in IMR-32 (GD2+) neuroblastoma cell line by CellTiter-Blue® cell viability assay after 72 h treatment. DAC-carbamate corresponds to an anti-GD2 / RBM39 DAC prepared using linker-modified payload JKW-68, whilst DAC-alkyl sulfonamide was generated using linker-modified payload JKW-162. Both DACs comprise of dinutuximab beta antibody (an antibody characterized by HC according to SEQ ID NO.: 15 and LC according to SEQ ID NO.: 16). Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted. Error bars represent SD. This experiment was performed twice, in technical triplicates, with similar results obtained each time. Representative data from one experiment are shown. ECso values were calculated using log(inhibitor) vs. response -- variable slope equation in GraphPad Prism 10 software.

[0082] Fig. 16 concerns in vitro anti-cancer activity of the synthesized library of E7820 RBM39 MGD analogs evaluated in MYC / V-amplified GD2+IMR-32 neuroblastoma cell line. IMR-32 cells were treated in 96-well plates with E7820 and three additional synthesized analogs for comparison (four compounds per plate) (a) JKW-126, JKW-131 , JKW-135, (b) JKW-112, JKW-142, indisulam, (c) JKW-132, JKW-168, JKW-174, (d) JKW-132, JKW-164, JKW-165 or (e) JKW-175, JKW-178, JKW-179 for 72 h and the cell viability was then evaluated by CellTiter-Blue® cell viability assay. Percentages of the viable neuroblastoma cells normalized to vehicle-treated controls were plotted. Error bars represent SD. ECso values were calculated using log(inhibitor) vs. response - - variable slope equation in GraphPad Prism 10 software. Detailed description of the invention

[0083] As already detailed herein above, the present invention relates to immunoconjugates comprising: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen (herein also “moiety (a)”); and b) a compound according to formula (I) as shown herein below (herein also “moiety (b)”).

[0084] In the embodiments of the present invention, said “moiety (a)” and said “moiety (b)” are linked, i.e. covalently linked in the inventive immunoconjugate(s). This applies, mutatis mutandis, to all inventive immunoconjugates of the present invention.

[0085] In particular, the present invention provides for (an) immunoconjugate(s) comprising: a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety that binds to a tumor antigen and / or to a cancer antigen, whereby said tumor and / or cancer antigen is preferably displayed on / expressed on the surface of a tumor and / or cancer cell; and b) a compound capable of inducing degradation of RBM39 oncoprotein, as provided herein by a compound according to formula (I).

[0086] Accordingly, the present invention provides for an immunoconjugate comprising a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety binding to a tumor antigen and / or to a cancer antigen; and b) a compound' according to formula (I): wherein

[0087] R1is selected from -H, C1-5 alkyl, -OH, -CN and -NO2; R2is selected from -H, halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -CN, -NO2, -CHO, -COOH, -COO(Ci-

[0088] 5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);

[0089] R3is selected from -H, halogen, C1-5 alkyl, aryl, -OH, -0(C1-5 alkyl), -CN, -NO2, -NH2, -NH(Ci-s alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), - CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(Ci.5alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);

[0090] R4is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(C1-5 alkyl), -N(CI-5 alkyl)(Ci-

[0091] 5alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONHfC^ alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);

[0092] R5is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci-

[0093] 5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -C0NH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(CI-5 alkyl)(C1-5 alkyl); and

[0094] A is a phenyl or five- or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs; and each Rsis independently selected from halogen, C1-5 alkyl, C1.5 haloalkyl, -OH, -0(C1-5 alkyl), -(C1-

[0095] 5 alkylene)-OH, -CN, -NH2, -(C1-5 alkylene)-NH2, -(C1.5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)- N(C1-5 alkyl)(C1-5 alkyl), -0-(C1-5 alkylene)-NH2, -O-(C2-5 alkylene)-N H(C1-5 alkyl), -O-(C2-5 alkylene)- N(CI-5 alkyl)(C1-5 alkyl), -N02, -NH(Ci_5alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci-5alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and - SO2N(C1-5 alkyl)(C1-5 alkyl).

[0096] In one embodiment of the invention, tumor antigen and / or cancer antigen to be targeted (bound by the antibody, the antibody fragment, the antibody construct, and / or the binding moiety) is expressed and / or displayed on the surface of a tumor and / or cancer cell. As used herein the terms “displayed on the surface of a tumor and / or cancer cell" and “expressed on the surface of a tumor and / or cancer cell" are used synonymously and interchangeably.

[0097] As is shown herein, in a preferred embodiment of the present invention, said binding “moiety (a)” which binds to targets said tumor antigen and / or a cancer antigen is an antibody, an antibody fragment or an antibody construct. The person skilled in the art is aware that the term “antibody” as used in context of immunoconjugates can also comprise “antibody fragments” and / or “antibody constructs”. The terms “antibodies”, as well as “antibody fragments” and / or “antibody constructs” are also further explained herein below. As illustrated in the non-limiting examples, in a preferred embodiment of the present invention, a full-length antibody that binds to the desired tumor antigen and / or cancer antigen may be employed in “moiety (a)” of the immunoconjugates of the present invention.

[0098] For example, suitable antibodies in “moiety (a)”, are inter alia, antibodies binding to a tumor antigen and / or a cancer antigen displayed on the surface of (a) tumor / cancer cell.

[0099] Suitable compounds capable of inducing degradation of RBM39, as defined herein, are described below and are also known in the art. A preferred compound to be used in “moiety (b)” is the compound according to formula (I). Therefore, a particularly suitable compound capable of inducing degradation of RBM39 is a compound as, inter alia, provided in formula (I), as described herein.

[0100] Thus, the present invention relates, in particular, to an immunoconjugate comprising a) an antibody, an antibody fragment, and / or an antibody construct that binds to a tumor antigen and / or to a cancer antigen, whereby said tumor and / or to a cancer antigen is displayed on the surface of a tumor and / or cancer cell; and b) a compound according to formula wherein

[0101] R1is selected from -H, C1-5 alkyl, -OH, -CN and -NO2;

[0102] R2is selected from -H, halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -CN, -NO2, -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and - SO2N(C1-5 alkyl)(C1-5 alkyl);

[0103] R3is selected from -H, halogen, C1-5 alkyl, aryl, -OH, -O(C1-5 alkyl), -CN, -NO2, -NH2, -NH(C1-5 alkyl), - N(CI-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(Ci- 5 alkyl), -SO2NH2, -SO2NH(CI-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl); R4is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(CI-5 alkyl), -N(Ci-s alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, - SO2NH(C1-5 alkyl) and -SOzNfCvs alkyl)(C1-5 alkyl);

[0104] R5is selected from -H, halogen, C1.5 alkyl, aryl, -CN, -NO2, -NH2, -NH(CI-5 alkyl), -N(Ci-s alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci.5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, - SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);

[0105] A is a phenyl or five- or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs; and each Rsis independently selected from halogen, C1-5 alkyl, C1.5 haloalkyl, -OH, -O(C1-5 alkyl), -(C1-5 alkylene)-OH, -CN, -NH2, -(C1-5 alkylene)-NH2, -(C1.5 alkylene)-NH(C1-5 alkyl), -(C1.5 alkylene)-N(Ci-s alkyl)(C1-5 alkyl), -O-(C1-5 alkylene)-NH2, -O-(C2-5 alkylene)-NH(C1-5 alkyl), -O-(C2-5 alkylene)-N(Ci-s alkyl)(C1-5 alkyl), -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci.5alkyl), -CONH2, -CONH(CI-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(Ci-5alkyl).

[0106] It has surprisingly been found in context of the present invention and as is illustrated in the appended examples that the means and methods provided herein, i.e., the herein described immunoconjugates of the invention, are characterized by providing an improved tumor and / or cancer therapy. Such an improved cancer therapy is illustrated in context of neuroblastoma / pediatric neuroblastoma by the herein provided anti-GD2 / RBM39 immunoconjugates (also described herein as “anti-GD2 / RBM39 degrader-antibody conjugates” / ”anti-GD2 / RBM39 DACs”). Such unexpected improvements comprise enhancement of treatment efficacy when antibody therapy, in particular when an anti-GD2 immunotherapy (here with inventive, yet illustrative, anti-GD2 / RBM39 DACs / anti-GD2 / RBM39 immunoconjugates) is employed. As is shown herein, the specifically claimed therapeutic approaches employing immunoconjugates of the invention can, inter alia, lead to the preferred use of minimal and reduced dosages of (in particular) therapeutically active antibodies, like anti-GD2 antibodies. Since such antibodies per se are known to induce undesired side effects, one of the gists of the present invention is that reduced amount of these antibodies (as proved herein in form of the immunoconjugates of the invention) can be medically employed in vivo which, in turn, enables the skilled artisan to achieve successful medical interventions. Preferably, and in one embodiment of the present invention, the inventive immunoconjugates as disclosed and provided herein display less undesired / unwanted side effects compared to the non-conjugated antibody counterparts and / or to the isolated RBM39 degrader. This is also illustrated and documented in the appended examples. The immunoconjugate of the invention comprises a) an antibody binding to a tumor antigen (such as GD2) displayed on the surface of a tumor / cancer cell.

[0107] As understood herein, the term “binding to" as used in the context of the present invention defines a binding (interaction) of at least two “antigen-interaction-sites” with each other. The term “antigeninteraction-site” defines, in accordance with the present invention, a motif in or a part of the of antibody, the antibody fragment, and / or the antibody construct in “moiety (a)” of the immunoconjugates which shows the capacity of specific interaction with a specific tumor / cancer antigen or a specific group of tumor / cancer antigens displayed on the surface of a tumor and / or cancer cell. Preferably, said binding is to be understood as specific binding. Of note and in context of this invention, the tumor antigen and / or cancer antigen as referred to in a) (“moiety (a)” of the inventive immunoconjugate), is also understood as being “targeted by a binding molecule”. Accordingly, and in context of this invention, the term “binding to” can also comprise a specific “targeting” of the (tumor / cancer) antigen by said antibody, the antibody fragment, and / or the antibody construct, preferably (but not limiting) by said antibody, which may be a full-length antibody. Accordingly, said tumor and / or cancer antigen may also be “targeted by” the antibody, the antibody fragment, and / or the antibody construct of “moiety (a)” of the inventive immunoconjugate(s). As explained herein, said binding to / targeting function in "moiety (a)” may also be fulfilled by an antibody fragment, an antibody construct or a binding moiety that comprises, inter alia and for example, the CDRs of a useful antibody that is capable of binding to / targeting an epitope on a desired tumor antigen and / or cancer antigen. In other words, the term “(binding) antibody” may also comprise, binding molecules or binding molecule stretches that are capable of binding to and / or target the desired relevant (tumor) antigen even if these are not full-length antibodies. Such binding molecules or binding molecule stretches may, for example comprise antibody fragments, antibody constructs, etc..

[0108] Accordingly, the notion that an antibody, an antibody fragment, and / or an antibody construct “specifically binds” to a certain target antigen (or an epitope thereof) is well-known in the art. In particular, an antibody can be said to “specifically bind” to a certain target antigen (or epitope) if it binds to said target antigen (or epitope) with greater affinity, avidity, more readily, and / or with greater duration (preferably with greater affinity) than it binds to other alternative antigens. Moreover, an antibody that “specifically binds” to a certain epitope (of an antigen) may be an antibody that binds to this epitope with greater affinity, avidity, more readily, and / or with greater duration (preferably with greater affinity) than it binds to other epitopes of the same antigen. It will be understood that “specific binding" does not necessarily require exclusive binding to the corresponding target, although such exclusive (or nearly exclusive) binding is generally desirable. An antibody, an antibody fragment, and / or an antibody construct that specifically binds to a first antigen may or may not specifically bind to a second antigen (which is different from the first antigen). In some embodiments, an antibody, an antibody fragment, and / or an antibody construct that “specifically binds” to a target antigen does not (or does not significantly) bind to other antigens (or, analogously, an antibody that “specifically binds" to a certain epitope may not, or may not significantly, bind to other epitopes in the same antigen), which may be reflected, e.g., in that only baseline binding activity can be detected for other antigens (or other epitopes).

[0109] As used herein, the term “epitope” refers to the site on a target antigen that is recognized and bound by an antibody. An epitope may be linear and, in that case, may typically have a length of 6 to 15 amino acid residues. This is in particular the case for antigens which are proteins or peptides. Alternatively, an epitope can be conformational. The epitope, as defined herein and in the context of the present invention, may also be a carbohydrate epitope, as in the case of GD2 disialoganglioside. The epitope to which an antibody (or an antigen-binding fragment) binds can be determined by routine methods, e.g., by epitope mapping methods, as also described further below.

[0110] As used herein, “tumor antigen” refers to a molecule that is present in cancer cells, but absent from normal (non-cancerous) cells. As it is further appreciated by the person skilled in the art, a tumor antigen may also show low abundance in normal, non-cancerous cells, but high expression in cancer cells. Particularly relevant in the context of the present invention are tumor antigens that are displayed on the surface of the cancer cell. Particularly preferred such tumor-specific antigens are described in the following. The tumor antigen is preferably a protein. However, the tumor antigen is not limited to protein, and tumor antigens that are e.g. sugar or glycolipid molecules, are also known.

[0111] As mentioned before, the herein exemplified and targeted tumor antigen (like, e.g., GD2) is preferably displayed on the surface of a cancer cell and / or a tumor cell. Such an “targeted tumor antigen” is bound by the “moiety (a)” of the inventive immunoconjugates.

[0112] As referred to herein, the tumor and / or cancer cell is not particularly limited and the antibody, the antibody fragment, the antibody construct (i.e. an antibody moiety comprising the antigen-binding side of an antibody that specifically binds to / targets the respective tumor / cancer antigen and / or the (preferably proteinaceous) binding moiety comprised in the inventive immunoconjugate of the invention as “moiety (a)" may be targeting / binding to any cancer and / or tumor cell. It is, however, preferred that the cancer cell / tumor cell, as referred to herein, is selected from a neuroblastoma cell, an Ewing sarcoma cell, an osteosarcoma cell, a medulloblastoma cell, brain cancer cell (such as glioma cell), a leukemia cell (such as AML cell or B-ALL cell, preferably AML cell), a rhabdomyosarcoma cell, a melanoma cell, a breast cancer cell, a triple negative breast cancer cell, a lung cancer cell, a colorectal cancer cell (such as colorectal adenoma cell), an ovarian cancer cell, a multiple myeloma cell, a hepatocellular carcinoma cell, pancreatic cancer cell, prostate cancer cell, bladder cancer cell, urethral cancer cell, cervical cancer cell, a soft tissue sarcoma cell and a lymphoma cell. These cancer / tumor cells are and / or are derived from solid tumors or hematologic malignancies (such as AML or B-ALL) which are characterized by high RBM39 expression, and growth and survival dependency on RBM39 RNA splicing factor (as illustrated in Table 1 , infra). Preferably, the tumor / cancer cell is selected from a neuroblastoma cell, an Ewing sarcoma cell, an osteosarcoma cell, a medulloblastoma cell, a glioma cell, a rhabdomyosarcoma cell, a melanoma cell, a triple negative breast cancer cell, a lung cancer cell and an ovarian cancer cell. These solid tumors are characterized by increased GD2 expression. As referred to herein, the colorectal cancer cell is preferably a colorectal adenoma cell. As further referred to herein, a brain cancer cell is not particularly limited and may refer to any brain cancer. It is however preferred that the brain cancer cell to be targeted by the inventive immunoconjugate(s) is a medulloblastoma cell or a glioma cell, preferably a medulloblastoma cell.

[0113] Particularly preferred as target cancer cell / tumor cell is a cancer cell / tumor cell expressing RBM39. RBM39 refers to the pre-mRNA splicing factor RNA-binding motif protein 39 (RBM39). This protein is known to the skilled person. Its protein sequence can be retrieved from the UniProt database under UniProt code Q14498. This protein is an RNA binding protein and possibly a splicing factor. The RBM39 protein is found in the nucleus, where it colocalizes with core spliceosomal proteins. Studies of a mouse protein with high sequence similarity to this protein suggest that this protein may act as a transcriptional coactivator for JUN / AP-1 and estrogen receptors. Multiple transcript variants encoding different isoforms have been observed for this gene.

[0114] Several cancers have been shown to be dependent on RBM39. These are summarized and illustrated in following Table 1. In each of the cancers referred to in Table 1 , RBM39 is overexpressed. Accordingly, suitable targetable cell surface antigens (tumor and / or cancer antigens) as well as -characteristic to the tumors / cancers are provided herein, inter alia, in following Table 1. Table 1.

[0115] Role of RBM39 in selected cancers (adapted from C. Xu et al.1) with a selection of surface antigens to be targeted in context of the herein provided immunoconjugates or DACs. Accordingly, and in context of this invention also these surface antigens can relevantly be targeted by the immunoconjugates, i.e, DACs and in particular the RBM39 DACS provided in context of this invention. “Moiety (a)” of the inventive immunoconjugates binds to / targets these tumor / cancer surface antigens. aADC-based targeted therapy approved by FDA or EMA. '’Antibody-based immunotherapy approved by FDA or EMA.cADC- based targeted therapy in a clinical trial. In Table 1, supra, the most dominant tumor / cancer cell surface antigens of the relevant tumors are listed.

[0116] Bolding indicates the main target of the immunoconjugates as provided herein. However, it is evident that the inventive immunoconjugates of the present invention may also comprise an antibody / antibody fragment / antibod'y construct (also considered in context of this invention as an “antibody moiety”) and / or binding moiety (i.e. a “moiety (a)” of the inventive immunoconjugate(s))that target the second or the third prominently expressed tumor / cancer antigen as listed above in Table 1. As is evident from the above, tumors / cancers to be treated with the immunoconjugates of the present invention may also comprise additional antigens than first mentioned prominent one. In other words, immunoconjugates of the present invention can also be employed in a medical setting when targeting not merely the most abundantly expressed (tumor / cancer) antigen on the surface of the tumor / cancer cells. For example, and without being limiting, neuroblastomas can be targeted not only with antibodies / immunoconjugates as provide herein that bind to GD2, but also with inventive immunoconjugates that bind to, e.g., B7-H3.

[0117] The immunoconjugates of the present invention can also be employed in the medical intervention of AML. In this context the skilled artisan would employ an immunoconjugate of the present invention, wherein the antibody / the antibody fragment / the antibody construct / the binding moiety (“moiety (a)" of the inventive immunoconjugate) binds to / targets CD33. Accordingly, as is evident and without departing form the gist of the present invention, in context of, e.g., leukemia treatment / AML treatment and / or prevention, the inventive immunoconjugate can also comprise an antibody / antibody construct / binding moiety that binds to, e.g. the cancer antigens CD123 or CLL-1 ; see Table 1 , supra.

[0118] The immunoconjugate / DAC of the present invention, comprises, in one embodiment, an antibody / antibody fragment / antibody construct / binding moiety that binds to a (tumor and / or cancer) antigen displayed and / or expressed on the surface of a tumor and / or cancer cell that expresses RBM39. Preferably, such cell expressing RBM39 is a cell overexpressing RBM39. Said antibody / antibody fragment / antibody construct / binding moiety binds to a tumor and / or cancer antigen that is displayed / expressed on the surface of such a cell. Suitable tumor and / or cancer antigens to be targeted by the immunoconjugate of the present invention are disclosed herein, see, e.g. Table 1 , supra. Suitable tumors and / or cancers, the tumor / cancer cells of which are dependent on RBM39 are also described in Table 1 , supra, in a non-limiting fashion. Accordingly, illustrative tumor and / or cancer antigens displayed on the surface of these tumor / cancer cells are not only provided and summarized in Table 1 , but also described hereinbelow.

[0119] Thus, according to the present invention, the tumor / cancer antigen to be bound by “moiety (a)” of the immunoconjugates of the present invention may be selected from GD2, O-acetyl-GD2 (such as 7-0- acetyl-GD2 or 9-O-acetyl-GD2), B7-H3, ALK„ CD33, GPC2, Trop-2, CD123, CLL-1 , STEAP1 , c-KIT, HER2, HER3, EGFR, FR-a and MUC16. In other words, the tumor / cancer antigen to be targeted by the immunoconjugate of the present invention may be, preferably, selected from GD2, O-acetyl-GD2 (such as 7-O-acetyl-GD2 or 9-O-acetyl-GD2), B7-H3, CD33, GPC2, ALK, Trop-2, CD123, CLL-1 , STEAP1 , c- KIT, HER2, HER3, EGFR, FR-a and MUC16.

[0120] Further known tumor / cancer antigens include R0R1 , ROR2, CEACAM5, CEACAM6, Nectin-4, CD19, CD22, CD30, CD37, CD79b, CD142, CD166, B7-H4, BCMA, 5T4, PSMA, NaPi2b, c-Met, claudin 18.2, claudin 3, claudin 4, claudin 6, integrin beta-6, mesothelin, AXL, LIV-1 , FLT3, CA9, DLL3 and PD-L1. Accordingly, it is also within the gist of the present invention that the inventive immunoconjugate comprises antibody binding moieties / binding moieties (i.e., an “moiety (a)” of the inventive immunoconjugate(s)) that target the immunoconjugate to such tumor antigens which are displayed on the surface of the corresponding tumor / cancer cell.

[0121] As understood herein, the tumor antigen GD2 is a disialoganglioside, also referred to as “ganglioside GD2”. It is expressed on tumors of neuroectodermal origin, including human neuroblastoma and melanoma, with highly restricted expression on normal tissues, principally to the cerebellum and peripheral nerves in humans. The relatively tumor-specific expression of GD2 makes it a suitable target for immunotherapy with monoclonal antibodies or with artificial T cell receptors. The term GD2 may refer to GD2 or its O-acetylated form, which can also be referred to as O-acetyl-GD2. Preferably, unless indicated to the contrary, the term GD2 refers to non-acetylated form of GD2, as defined in the following. Accordingly, GD2 may refer to a non-acetylated form of said ganglioside, which can be defined by its chemical name: (2R,4R,5S,6S)-2-[3-[(2S,3S,4R,6S)-6-[(2S,3R,4R,5S,6R)-5-[(2S,3R,4R,5R,6R)-3- acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-[(2R,3S,4R,5R,6R)-4,5-dihydroxy-2- (hydroxymethyl)-6-[(E)-3-hydroxy-2-(octadecanoylamino)octadec-4-enoxy]oxan-3-yl]oxy-3-hydroxy-6- (hydroxymethyl)oxan-4-yl]oxy-3-amino-6-carboxy-4-hydroxyoxan-2-yl]-2,3-dihydroxypropoxy]-5-amino- 4-hydroxy-6-(1 ,2,3-trihydroxypropyl)oxane-2-carboxylic acid. Said GD2 may also be defined structurally, as being according to formula:

[0122] Alternatively, the term GD2 may also refer to acetylated version of GD2, also referred to as O-acetyl-GD2. Different types of O-acety I modification of GD2 exist and include 7-O-acetyl-GD2 and 9-O-acetyl-GD2. As understood herein, 9-O-acetyl-GD2 is a compound according to formula: As further understood herein, 7-O-acetyl-GD2 is a compound according to formula:

[0123]

[0124] If reference is made to 0-acetyl-GD2 or acetylated form of GD2, a reference is thereby made to 7-0- acetyl-GD2 and / or 9-O-acetyl-GD2. Such reference may also be understood as a reference made individually to 7-O-acetyl-GD2, or a reference made individually to 9-O-acetyl-GD2.

[0125] The tumor / cancer antigen to be bound / targeted by “moiety (a)” of the inventive immunoconjugates may also be a protein, including receptor proteins. Such tumor and / or cancer antigens to be bound / targeted by “moiety (a)” of the inventive immunoconjugates may be also selected from B7-H3, CD33, GPC2, ALK, Trop-2, CD123, CLL-1 , STEAP1 , c-KIT, HER2, HER3, EGFR, FR-a and MLIC16.

[0126] As mentioned before, these tumor / cancer antigens (to be target by “moiety (a) of the inventive immunoconjugates) are particularly useful in the context of the present invention. In other words, the tumor / cancer antigen to be targeted by the immunoconjugate of the present invention may not only target GD2, but also (surface) antigens on tumors / cancer cells that are selected from the group consisting of, e.g„ B7-H3, CD33, GPC2, ALK, Trop-2, CD123, CLL-1 , STEAP1 , c-KIT, HER2, HER3, EGFR, FR-a and MUC16.

[0127] Accordingly, said tumor / cancer antigen, understood as the tumor / cancer antigen to be targeted by the antibody / antibody fragment / antibody construct “moiety (a)" of the immunoconjugate of the present invention, may also be B7-H3. B7-H3 is type I transmembrane protein, existing in two isoforms determined by its extracellular domain. In humans, the extracellular domain consists of one pair (2lg-B7-H3) or two identical pairs (4lg-B7-H3) due to exon duplication. B7-H3 mRNA is expressed in most normal tissues. In contrast, B7-H3 protein has a very limited expression on normal tissues because of its post-transcriptional regulation by microRNAs. However, B7-H3 protein is expressed at high frequency on many different cancer types (60% of all cancers). The 4lg-B7-H3 isoform is predominant in cancer. The tumor antigen B7-H3 is characterized by an amino acid sequence according to SEQ ID NO.: 1. B7-H3 (SEQ ID NO.: 1):

[0128] MLRRRGSPGMGVHVGAALGALWFCLTGALEVQVPEDPVVALVGTDATLCCSFSPEPGFSLAQLNLIWQLTDTKQL I

[0129] VHSFAEGQDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFVS IRDFGSAAVSLQVAAPYSKPSMTLE I

[0130] PNKDLRPGDTVTITCSSYQGYPEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSILRVVLGANGTYSCLVRNP (

[0131] VLQQDAHSSVTITPQRSPTGAVEVQVPEDPVVALVGTDATLRCSFSPEPGFSLAQLNLIWQLTDTKQLVHSFTEG |

[0132] RDQGSAYANRTALFPDLLAQGNASLRLQRVRVADEGSFTCFVSIRDFGSAAVSLQVAAPYSKPSMTLEPNKDLRP [

[0133] GDTVTITCSSYRGYPEAEVFWQDGQGVPLTGNVTTSQMANEQGLFDVHSVLRVVLGANGTYSCLVRNPVLQQDAH |

[0134] GSVTITGQPMTFPPEALWVTVGLSVCLIALLVALAFVCWRKIKQSCEEENAGAEDQDGEGEGSKTALQPLKHSDS I

[0135] KEDDGQEIA [

[0136] The tumor antigen, understood as the tumor antigen to be targeted by the antibody “moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be glypican 2 (GPC2), also known as cerebroglycan. Cerebroglycan is | a glycophosphatidylinositol-linked integral membrane heparan sulfate proteoglycan found in the developing nervous system. Cerebroglycan participates in cell adhesion and is thought to regulate the growth and guidance of axons, Cerebroglycan has especially high affinity for laminin-1 . GPC2 has been identified as a therapeutic target in neuroblastoma in two independent studies published by Mitchell Ho's lab at the NCI and John Maris's lab at the University of Pennsylvania in 2017. GPC2 is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival.

[0137] The tumor antigen GPC2 is characterized by an amino acid sequence according to SEQ ID NO.: 2.

[0138] I

[0139] GPC2 (SEQ ID NO.: 2):

[0140] MSALRPLLLLLLPLCPGPGPGPGSEAKVTRSCAETRQVLGARGYSLNLI PPALISGEHLRVCPQEYTCCSSETEQ I

[0141] RLIRETEATFRGLVEDSGSFLVHTLAARHRKFDEFFLEMLSVAQHSLTQLFSHSYGRLYAQHALIFNGLFSRLRD FYGESGEGLDDTLADFWAQLLERVFPLLHPQYSFPPDYLLCLSRLASSTDGSLQPFGDSPRRLRLQITRTLVAAR AFVQGLETGRNVVSEALKVPVSEGCSQALMRLIGCPLCRGVPSLMPCQGFCLNVVRGCLSSRGLEPDWGNYLDGL LILADKLQGPFSFELTAESIGVKISEGLMYLQENSAKVSAQVFQECGPPDPVPARNRRAPPPREEAGRLWSMVTE I

[0142] EERPTTAAGTNLHRLVWELRERLARMRGFWARLSLTVCGDSRMAADASLEAAPCWTGAGRGRYLPPVVGGSPAEQ VNNPELKVDASGPDVPTRRRRLQLRAATARMKTAALGHDLDGQDADEDASGSGGGQQYADDWMAGAVAPPARPPR PPYPPRRDGSGGKGGGGSARYNQGRSRSGGASIGFHTQTILILSLSALALLGPR

[0143] The tumor antigen, understood as the tumor antigen to be targeted by the antibody "moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of then the immunoconjugate of the present invention, may also be ALK. Anaplastic lymphoma kinase (ALK) is also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246). Anaplastic lymphoma kinase (ALK) was originally discovered in 1994 in anaplastic large-cell lymphoma (ALCL) cells. ALCL is caused by a (2;5)(p23:q35) chromosomal translocation that generates the fusion protein NPM-ALK, in which the kinase domain of ALK is fused to the amino-terminal part of the nucleophosmin (NPM) protein. Dimerization of NPM constitutively activates the ALK kinase domain. The full-length protein ALK was identified in 1997. The deduced amino acid sequences revealed that ALK was a novel receptor tyrosine kinase (RTK), having an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. While the tyrosine kinase domain of human ALK shares a high degree of similarity with that of the insulin receptor, its extracellular domain is unique among the RTK family in containing two MAM domains (meprin, A5 protein and receptor protein tyrosine phosphatase mu), an LDLa domain (low-density lipoprotein receptor class A) and a glycine-rich region. Based on overall homology, ALK is closely related to the leukocyte receptor tyrosine kinase (LTK) and, together with the insulin receptor, forms a subgroup in the RTK superfamily. The receptor ALK plays a pivotal role in cellular communication and in the normal development and function of the nervous system. This observation is based on the extensive expression of ALK messenger RNA (mRNA) throughout the nervous system during mouse embryogenesis. In vitro functional studies have demonstrated that ALK activation promotes neuronal differentiation of PC12 or neuroblastoma cell lines. The tumor antigen ALK is characterized by an amino acid sequence according to SEQ ID NO.: 3.

[0144] ALK (SEQ ID NO.: 3): MGAIGLLWLLPLLLSTAAVGSGMGTGQRAGSPAAGPPLQPREPLSYSRLQRKSLAVDFVVPSLFRVYARDLLLPP SSSELKAGRPEARGSLALDCAPLLRLLGPAPGVSWTAGSPAPAEARTLSRVLKGGSVRKLRRAKQLVLELGEEAI LEGCVGPPGEAAVGLLQFNLSELFSWWIRQGEGRLRIRLMPEKKASEVGREGRLSAAIRASQPRLLFQIFGTGHS SLESPTNMPSPSPDYFTWNLTWIMKDSFPFLSHRSRYGLECSFDFPCELEYSPPLHDLRNQSWSWRRI PSEEASQ MDLLDGPGAERSKEMPRGSFLLLNTSADSKHTILSPWMRSSSEHCTLAVSVHRHLQPSGRYIAQLLPHNEAAREI LLMPTPGKHGWTVLQGRIGRPDNPFRVALEYISSGNRSLSAVDFFALKNCSEGTSPGSKMALQSSFTCWNGTVLQ LGQACDFHQDCAQGEDESQMCRKLPVGFYCNFEDGFCGWTQGTLSPHTPQWQVRTLKDARFQDHQDHALLLSTTD VPASESATVTSATFPAPIKSSPCELRMSWLIRGVLRGNVSLVLVENKTGKEQGRMVWHVAAYEGLSLWQWMVLPL LDVSDRFWLQMVAWWGQGSRAIVAFDNISISLDCYLTISGEDKILQNTAPKSRNLFERNPNKELKPGENSPRQTP IFDPTVHWLFTTCGASGPHGPTQAQCNNAYQNSNLSVEVGSEGPLKGIQIWKVPATDTYSISGYGAAGGKGGKNT MMRSHGVSVLGI FNLEKDDMLYILVGQQGEDACPSTNQLIQKVCIGENNVIEEEIRVNRSVHEWAGGGGGGGGAT YVFKMKDGVPVPLI IAAGGGGRAYGAKTDTFHPERLENNSSVLGLNGNSGAAGGGGGWNDNTSLLWAGKSLQEGA TGGHSCPQAMKKWGWETRGGFGGGGGGCSSGGGGGGYIGGNAASNNDPEMDGEDGVSFISPLGILYTPALKVMEG HGEVNIKHYLNCSHCEVDECHMDPESHKVICFCDHGTVLAEDGVSCIVSPTPEPHLPLSLILSVVTSALVAALVL AFSGIMIVYRRKHQELQAMQMELQSPEYKLSKLRTSTIMTDYNPNYCFAGKTSSISDLKEVPRKNITLIRGLGHG AFGEVYEGQVSGMPNDPSPLQVAVKTLPEVCSEQDELDFLMEALI I SKFNHQNIVRCIGVSLQSLPRFILLELMA GGDLKSFLRETRPRPSQPSSLAMLDLLHVARDIACGCQYLEENHFIHRDIAARNCLLTCPGPGRVAKIGDFGMAR DIYRASYYRKGGCAMLPVKWMPPEAFMEGI FTSKTDTWSFGVLLWEI FSLGYMPYPSKSNQEVLEFVTSGGRMDP PKNCPGPVYRIMTQCWQHQPEDRPNFAI ILERIEYCTQDPDVINTALPIEYGPLVEEEEKVPVRPKDPEGVPPLL VSQQAKREEERSPAAPPPLPTTSSGKAAKKPTAAEISVRVPRGPAVEGGHVNMAFSQSNPPSELHKVHGSRNKPT

[0145] SLWNPTYGSWFTEKPTKKNNPIAKKEPHDRGNLGLEGSCTVPPNVATGRLPGASLLLEPSSLTANMKEVPLFRLR

[0146] HFPCGNVNYGYQQQGLPLEAATAPGAGHYEDTILKSKNSMNQPGP

[0147] Including most common mutations occurring at three hotspots within the tyrosine kinase domain: F1174L (or alternatively to C, S, V or I), F1245V (or alternatively to I, C, Y or L) and R1275Q (or alternatively to L). These mutations are the most frequent mutations occurring in neuroblastoma. Further mutations commonly occurring in other malignancies include G1202R (or deletion), L1196M, L1152R, C1156Y, G1269A and I1171 N (or alternatively to S or T).

[0148] The tumor antigen, understood as the tumor antigen to be targeted by the antibody “moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of then the immunoconjugate of the present invention, may also be HER2. Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 (human epidermal growth factor receptor 2) or CD340 (cluster of differentiation 340). HER2 is a member of the human epidermal growth factor receptor (HER / EGFR / ERBB) family. But contrary to other members of the ERBB family, HER2 does not directly bind ligand. HER2 activation results from heterodimerization with another ERBB member or by homodimerization when HER2 concentration is high, for instance in cancer. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years, HER2 receptor has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. The tumor antigen HER2 is characterized by an amino acid sequence according to SEQ ID NO.: 4.

[0149] HER2 (SEQ ID NO.: 4):

[0150] MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQVVQGNLELTYLPTNASLSFLQ DIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNYALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILK GGVLIQRNPQLCYQDTILWKDI FHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCA RCKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMPNPEGRYTFGASCVTACP YNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCARVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLA FLPESFDGDPASNTAPLQPEQLQVFETLEEITGYLYI SAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGI SWLGLRSLRELGSGLALI HHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACHQLCARGHCWGPGP TQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQPQNGSVTCFGPEADQCVACAHYKDPPFCVARC PSGVKPDLSYMPIWKFPDEEGACQPCPINCTHSCVDLDDKGCPAEQRASPLTSI ISAVVGILLVVVLGVVFGILI KRRQQKIRKYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIWI PDGENVKI PV AIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLVTQLMPYGCLLDHVRENRGRLGSQDLLNW CMQIAKGMSYLEDVRLVHRDLAARNVLVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFT HQSDVWSYGVTVWELMTFGAKPYDGIPAREI PDLLEKGERLPQPPICTIDVYMIMVKCWMIDSECRPRFRELVSE FSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEEYLVPQQGFFCPDPAPGAGGMVHHRHRSS STRSGGGDLTLGLEPSEEEAPRSPLAPSEGAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETD GYVAPLTCSPQPEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVENPEYLTPQ GGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGLDVPV

[0151] The tumor antigen, understood as the tumor antigen to be targeted by the antibody "moiety (a)” (i.e. an antibody, the antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be HER3. Receptor tyrosine-protein kinase erbB-3, also known as HER3 (human epidermal growth factor receptor 3), is a membrane bound protein that in humans is encoded by the ERBB3 gene. ErbB3 is a member of the epidermal growth factor receptor (EGFR / ERBB) family of receptor tyrosine kinases. The kinase-impaired ErbB3 is known to form active heterodimers with other members of the ErbB family, most notably the ligand binding-impaired ErbB2. The tumor antigen HER3 is characterized by an amino acid sequence according to SEQ ID NO.: 5.

[0152] HER3 (SEQ ID NO.: 5):

[0153] MRANDALQVLGLLFSLARGSEVGNSQAVCPGTLNGLSVTGDAENQYQTLYKLYERCEVVMGNLEIVLTGHNADLS FLQWIREVTGYVLVAMNEFSTLPLPNLRVVRGTQVYDGKFAI FVMLNYNTNSSHALRQLRLTQLTEILSGGVYIE KNDKLCHMDTIDWRDIVRDRDAEIVVKDNGRSCPPCHEVCKGRCWGPGSEDCQTLTKTICAPQCNGHCFGPNPNQ CCHDECAGGCSGPQDTDCFACRHFNDSGACVPRCPQPLVYNKLTFQLEPNPHTKYQYGGVCVASCPHNFVVDQTS CVRACPPDKMEVDKNGLKMCEPCGGLCPKACEGTGSGSRFQTVDSSNIDGFVNCTKILGNLDFLITGLNGDPWHK I PALDPEKLNVFRTVREITGYLNIQSWPPHMHNFSVFSNLTTIGGRSLYNRGFSLLIMKNLNVTSLGFRSLKEIS AGRIYI SANRQLCYHHSLNWTKVLRGPTEERLDIKHNRPRRDCVAEGKVCDPLCSSGGCWGPGPGQCLSCRNYSR GGVCVTHCNFLNGEPREFAHEAECFSCHPECQPMEGTATCNGSGSDTCAQCAHFRDGPHCVSSCPHGVLGAKGPI YKYPDVQNECRPCHENCTQGCKGPELQDCLGQTLVLIGKTHLTMALTVIAGLVVIFMMLGGTFLYWRGRRIQNKR AMRRYLERGESIEPLDPSEKANKVLARIFKETELRKLKVLGSGVFGTVHKGVWIPEGESIKIPVCIKVIEDKSGR QSFQAVTDHMLAIGSLDHAHIVRLLGLCPGSSLQLVTQYLPLGSLLDHVRQHRGALGPQLLLNWGVQIAKGMYYL EEHGMVHRNLAARNVLLKSPSQVQVADFGVADLLPPDDKQLLYSEAKTPIKWMALESIHFGKYTHQSDVWSYGVT VWELMTFGAEPYAGLRLAEVPDLLEKGERLAQPQICTIDVYMVMVKCWMIDENIRPTFKELANEFTRMARDPPRY LVIKRESGPGIAPGPEPHGLTNKKLEEVELEPELDLDLDLEAEEDNLATTTLGSALSLPVGTLNRPRGSQSLLSP SSGYMPMNQGNLGESCQESAVSGSSERCPRPVSLHPMPRGCLASESSEGHVTGSEAELQEKVSMCRSRSRSRSPR PRGDSAYHSQRHSLLTPVTPLSPPGLEEEDVNGYVMPDTHLKGTPSSREGTLSSVGLSSVLGTEEEDEDEEYEYM NRRRRHSPPHPPRPSSLEELGYEYMDVGSDLSASLGSTQSCPLHPVPIMPTAGTTPDEDYEYMNRQRDGGGPGGD YAAMGACPASEQGYEEMRAFQGPGHQAPHVHYARLKTLRSLEATDSAFDNPDYWHSRLFPKANAQRT The tumor antigen, understood as the tumor antigen to be targeted by the antibody “moiety (a)” (i.e. an antibody, the antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be Trop-2. Tumor-associated calcium signal transducer 2, also known as Trop-2 and as epithelial glycoprotein-1 antigen (EGP-1) is a protein that in humans is encoded by the TACSTD2 gene. This intronless gene encodes a carcinoma-associated antigen defined by the monoclonal antibody GA733. This antigen is a member of a family including at least two type I membrane proteins. It transduces an intracellular calcium signal and acts as a cell surface receptor. Mutations of this gene result in gelatinous drop-like corneal dystrophy, an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness. Trop-2 expression was originally described in trophoblasts (placenta) and fetal tissues (e.g., lung). Later, its expression was also described in the normal stratified squamous epithelium of the skin, uterine cervix, esophagus, and tonsillar crypts. Trop-2 plays a role in tumor progression by actively interacting with several key molecular signaling pathways traditionally associated with cancer development and progression. Aberrant overexpression of Trop-2 has been described in several solid cancers, such as colorectal, renal, lung, and breast cancer. Trop-2 overexpression has also been described in some rare and aggressive malignancies, e.g., salivary duct, anaplastic thyroid, uterine / ovarian, and neuroendocrine prostate cancers. The tumor antigen Trop-2 is characterized by an amino acid sequence according to SEQ ID NO.: 6.

[0154] Trop-2 (SEQ ID NO.: 6):

[0155] MARGPGLAPPPLRLPLLLLVLAAVTGHTAAQDNCTCPTNKMTVCSPDGPGGRCQCRALGSGMAVDCSTLTSKCLL LKARMSAPKNARTLVRPSEHALVDNDGLYDPDCDPEGRFKARQCNQTSVCWCVNSVGVRRTDKGDLSLRCDELVR THHILIDLRHRPTAGAFNHSDLDAELRRLFRERYRLHPKFVAAVHYEQPTIQIELRQNTSQKAAGDVDIGDAAYY FERDIKGESLFQGRGGLDLRVRGEPLQVERTLIYYLDEIPPKFSMKRLTAGLIAVIVWVVALVAGMAVLVITNR RKSGKYKKVEIKELGELRKEPSL

[0156] In a specific embodiment of the present invention, it is intended to treat and / or prevent leukemias (such as AML cell or B-ALL, preferably AML, i.e. acute myeloid leukemia) with immunoconjugates of the present invention. In context of this embodiment of the present invention, the tumor / cancer antigen to be targeted by the “moiety (a)” of the immunoconjugate of the present invention, may also be CD33. As apparent to the skilled artisan, antibodies (as well as antibody fragments and antibody constructs) targeting CD33 are particularly suitable as “moiety (a)” of the inventive immunoconjugates which are envisaged for therapeutic intervention of leukemias, in particular of AML. CD33 or Siglec-3 (sialic acid binding Ig-like lectin 3, SIGLEC3, SIGLEC-3, gp67, p67) is a transmembrane receptor expressed on cells of myeloid lineage. It is usually considered myeloid-specific, but it can also be found on some lymphoid cells. CD33 binds sialic acids, therefore it is a member of the SIGLEC family of lectins. The extracellular portion of this receptor contains two immunoglobulin domains (one IgV and one lgC2 domain), placing CD33 within the immunoglobulin superfamily. The intracellular portion of CD33 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that are implicated in inhibition of cellular activity. CD33 can be stimulated by any molecule with sialic acid residues such as glycoproteins or glycolipids. Upon binding, the immunoreceptor tyrosine-based inhibition motif (ITIM) of CD33, present on the cytosolic portion of the protein, is phosphorylated and acts as a docking site for Src homology 2 (SH2) domain-containing proteins like SHP phosphatases. This results in a cascade that inhibits phagocytosis in the cell CD33 is the target of gemtuzumab ozogamicin (trade name: Mylotarg®; Pfizer / Wyeth-Ayerst Laboratories), an antibody-drug conjugate (ADC) for the treatment of patients with acute myeloid leukemia. The drug is a recombinant, humanized anti-CD33 monoclonal antibody (lgG4 K antibody hP67.6) covalently attached to the cytotoxic anti-tumor antibiotic calicheamicin ( / V-acetyl-y-calicheamicin) via a bifunctional linker (4-(4- acetylphenoxy)butanoic acid). Several mechanisms of resistance to gemtuzumab ozogamicin have been elucidated. On September 1 , 2017, the FDA approved Pfizer's Mylotarg. Gemtuzumab ozogamicin was initially approved by the U.S. Food and Drug Administration in 2000. However, during post marketing clinical trials researchers noticed a greater number of deaths in the group of patients who received gemtuzumab ozogamicin compared with those receiving chemotherapy alone. Based on these results, Pfizer voluntarily withdrew gemtuzumab ozogamicin from the market in mid-2010, but it was reintroduced to the market in 2017. CD33 is also the target in Vadastuximab talirine (SGN-CD33A), a novel antibodydrug conjugate that was being developed by Seattle Genetics, utilizing this company's ADC technology. The cancer antigen CD33 is characterized by an amino acid sequence according to SEQ ID NO.: 7.

[0157] CD33 (SEQ ID NO.: 7):

[0158] MPLLLLLPLLWAGALAMDPNFWLQVQESVTVQEGLCVLVPCTFFHPI PYYDKNSPVHGYWFREGAI ISRDSPVAT NKLDQEVQEETQGRFRLLGDPSRNNCSLSIVDARRRDNGSYFFRMERGSTKYSYKSPQLSVHVTDLTHRPKILIP GTLEPGHSKNLTCSVSWACEQGTPPI FSWLSAAPTSLGPRTTHSSVLI ITPRPQDHGTNLTCQVKFAGAGVTTER TIQLNVTYVPQNPTTGI FPGDGSGKQETRAGVVHGAIGGAGVTALLALCLCLI FFIVKTHRRKAARTAVGRNDTH PTTGSASPKHQKKSKLHGPTETSSCSGAAPTVEMDEELHYASLNFHGMNPSKDTSTEYSEVRTQ

[0159] As also illustrated in Table 1 , supra, B-cell acute lymphoblastic leukemia (B-ALL) may also be a target for medical intervention with immunoconjugates of the present invention. In this embodiment of the present invention, “moiety (a)” could comprise an antibody, an antibody fragment, an antibody construct and / or a binding moiety as defined herein that binds to / targets a cancer antigen selected from the group consisting of CD22, CD19 and CD74. The tumor / cancer antigen , understood as the tumor / cancer antigen to be targeted by the antibody “moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be the cancer antigen CLL-1. CLL-1 stands for C- type lectin domain family 12 member A. In the immunotherapy of acute myeloid leukemia (AML), CLL-1 becomes one of the targets due to its high expression in AML cells while being absent in normal hematopoietic stem cells. CLL-1 is also expressed on the surface of leukemic stem cells (LSC), which possess the ability to indefinitely self-renew, produce plenty of leukemic cells and are associated with leukemia relapses. The cancer antigen CLL-1 is characterized by an amino acid sequence according to SEQ ID NO.: 8.

[0160] CLL-1 (SEQ ID NO.: 8):

[0161] MSEEVTYADLQFQNSSEMEKIPEIGKFGEKAPPAPSHVWRPAALFLTLLCLLLLIGLGVLASMFHVTLKIEMKKM NKLQNISEELQRNISLQLMSNMNI SNKIRNLSTTLQTIATKLCRELYSKEQEHKCKPCPRRWIWHKDSCYFLSDD VQTWQESKMACAAQNASLLKINNKNALEFIKSQSRSYDYWLGLSPEEDSTRGMRVDNIINSSAWVIRNAPDLNNM YCGYINRLYVQYYHCTYKKRMICEKMANPVQLGSTYFREA

[0162] The tumor antigen, understood as the tumor antigen to be targeted by the antibody “moiety (a)” (i.e. an antibody, the antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be c-KIT. Proto-oncogene c-KIT is the gene encoding the receptor tyrosine kinase protein known as tyrosine-protein kinase KIT, CD117 (cluster of differentiation 117) or mast / stem cell growth factor receptor (SCFR). Multiple transcript variants encoding different isoforms have been found for this gene. KIT was first described by the German biochemist Axel Ullrich in 1987 as the cellular homolog of the feline sarcoma viral oncogene v-kit. KIT is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. Altered forms of this receptor may be associated with some types of cancer.[9] KIT is a receptor tyrosine kinase type III, which binds to stem cell factor, also known as "steel factor" or "c-kit ligand". When this receptor binds to stem cell factor (SCF) it forms a dimer that activates its intrinsic tyrosine kinase activity, that in turn phosphorylates and activates signal transduction molecules that propagate the signal in the cell. After activation, the receptor is ubiquitinated to mark it for transport to a lysosome and eventual destruction. Signaling through KIT plays a role in cell survival, proliferation, and differentiation. For instance, KIT signaling is required for melanocyte survival, and it is also involved in hematopoiesis and gametogenesis. Cluster of differentiation (CD) molecules are markers on the cell surface, as recognized by specific sets of antibodies, used to identify the cell type, stage of differentiation and activity of a cell. KIT is an important cell surface marker used to identify certain types of hematopoietic (blood) progenitors in the bone marrow. To be specific, hematopoietic stem cells (HSC), multipotent progenitors (MPP), and common myeloid progenitors (CMP) express high levels of KIT. Common lymphoid progenitors (CLP) express low surface levels of KIT. KIT also identifies the earliest thymocyte progenitors in the thymus— early T lineage progenitors (ETP / DN1) and DN2 thymocytes express high levels of c-KIT. It is also a marker for mouse prostate stem cells. In addition, mast cells, melanocytes in the skin, and interstitial cells of Cajal in the digestive tract express KIT. In humans, expression of c-KIT in helper-like innate lymphoid cells (ILCs) which lack the expression of CRTH2 (CD294) is used to mark the ILC3 population. CD117 / c-KIT is expressed not only by bone marrow-derived stem cells, but also by those found in other adult organs, such as the prostate, liver, and heart, suggesting that SCF / c-KIT signaling pathways may contribute to sternness in some organs. Additionally, c-KIT has been associated with numerous biological processes in other cell types. For example, c-KIT signaling, has been shown to regulate oogenesis, folliculogenesis, and spermatogenesis, playing important roles in female and male fertility. Activating mutations in this gene are associated with gastrointestinal stromal tumors, testicular seminoma, mast cell disease, melanoma, acute myeloid leukemia, while inactivating mutations are associated with the genetic defect piebaldism. c-KIT plays an important role in regulating many mechanisms leading to tumor formation and progression of carcinomas. c-KIT has been proposed as a regulator of sternness in several cancers. Its expression has been linked to cancer sternness in ovarian cancer cells, colon cancer cells, non-small cell lung cancer cells, and prostate cancer cells. c-KIT has also been linked to the epithelial-mesenchymal transition (EMT), which is important for tumor aggressiveness and metastatic potential. Ectopic expression of c-KIT and EMT have been linked in adenoid cystic carcinoma of the salivary gland, thymic carcinomas, ovarian cancer cells, and prostate cancer cells. Several lines of evidence suggest that SCF / c-KIT signaling plays an important role in the tumor microenvironment. For example, in mice high levels of c-KIT in mast cells as well as its presence in the tumor microenvironment promote angiogenesis, leading to increased tumor growth and metastasis. The tumor antigen c-KIT is characterized by an amino acid sequence according to SEQ ID NO.: 9. c-KIT (SEQ ID NO.: 9):

[0163] MRGARGAWDFLCVLLLLLRVQTGSSQPSVSPGEPSPPSIHPGKSDLIVRVGDEIRLLCTDPGFVKWTFEILDETN ENKQNEWITEKAEATNTGKYTCTNKHGLSNSI YVFVRDPAKLFLVDRSLYGKEDNDTLVRCPLTDPEVTNYSLKG CQGKPLPKDLRFI PDPKAGIMIKSVKRAYHRLCLHCSVDQEGKSVLSEKFILKVRPAFKAVPVVSVSKASYLLRE GEEFTVTCTIKDVSSSVYSTWKRENSQTKLQEKYNSWHHGDFNYERQATLTISSARVNDSGVFMCYANNTFGSAN VTTTLEVVDKGFINI FPMINTTVFVNDGENVDLIVEYEAFPKPEHQQWIYMNRTFTDKWEDYPKSENESNIRYVS ELHLTRLKGTEGGTYTFLVSNSDVNAAIAFNVYVNTKPEILTYDRLVNGMLQCVAAGFPEPTIDWYFCPGTEQRC SASVLPVDVQTLNSSGPPFGKLVVQSS I DSSAFKHNGTVECKAYNDVGKTSAYFNFAFKGNNKEQIHPHTLFTPL LIGFVIVAGMMCI IVMILTYKYLQKPMYEVQWKVVEEINGNNYVYI DPTQLPYDHKWEFPRNRLSFGKTLGAGAF GKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNHMNIVNLLGACTIGGPTLVITEYCCY GDLLNFLRRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIER DVTPAIMEDDELALDLEDLLSFSYQVAKGMAFLASKNCTHRDLAARNILLTHGRITKICDFGLARDIKNDSNYVV KGNARLPVKWMAPESIFNCVYTFESDVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMY DIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPWDHSVRINSVGSTASSSQPLLVHDD V

[0164] The cancer antigen, understood as the tumor antigen to be targeted by the antibody “moiety (a)” (i.e. an antibody and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be CD123. The interleukin-3 receptor (CD123) is a molecule found on cells which helps transmit the signal of interleukin-3, a soluble cytokine important in the immune system. The gene coding for the receptor is located in the pseudoautosomal region of the X and Y chromosomes. The receptor belongs to the type I cytokine receptor family and is a heterodimer with a unique alpha chain paired with the common beta (beta c or CD131) subunit. The gene for the alpha subunit is 40 kilobases long and has 12 exons. The receptor, found on pluripotent progenitor cells, induces tyrosine phosphorylation within the cell and promotes proliferation and differentiation within the hematopoietic cell lines. It can be found on basophils and pDCs as well as some eDCs among peripheral blood mononuclear cells. CD123 is expressed across acute myeloid leukemia (AML) subtypes, including leukemic stem cells. The cancer antigen CD123 is characterized by an amino acid sequence according to SEQ ID NO.: 10.

[0165] CD123 (SEQ ID NO.: 10):

[0166] MKKEHVLHCQFSAWYPFFRGVTIKSVILPLPQNVKDYLLDDGTLVVSGRDDPPTHSQPDSDDEAEEIQWSDDENT ATLTAPEFPEFATKVQEAINSLGGSVFPKLNWSAPRDAYWIAMNSSLKCKTLSDIFLLFKSSDFITRDFTQPFIH CTDDSPDPCIEYELVLRKWCELIPGAEFRCFVKENKLIGISQRDYTQYYDHISKQKEEIRRCIQDFFKKHIQYKF LDEDFVFDIYRDSRGKVWLIDFNPFGEVTDSLLFTWEELISENNLNGDFSEVDAQEQDSPAFRCTNSEVTVQPSP YLSYRLPKDFVDLSTGEDAHKLIDFLKLKRNQQEDD

[0167] The tumor antigen, understood as the tumor antigen to be targeted by the “antibody moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be EGFR. The epidermal growth factor receptor (EGFR; ErbB-1 ; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands. The epidermal growth factor receptor is a member of the ErbB family of receptors, a subfamily of four closely related receptor tyrosine kinases: EGFR (ErbB- 1), HER2 / neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). In many cancer types, mutations affecting EGFR expression or activity could result in cancer. Epidermal growth factor and its receptor was discovered by Stanley Cohen of Vanderbilt University. Cohen shared the 1986 Nobel Prize in Medicine with Rita Levi-Montalcini for their discovery of growth factors. Deficient signaling of the EGFR and other receptor tyrosine kinases in humans is associated with diseases such as Alzheimer's, while overexpression is associated with the development of a wide variety of tumors. Interruption of EGFR signaling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumors and improve the patient's condition. The tumor antigen EGFR is characterized by an amino acid sequence according to SEQ ID NO.: 11.

[0168] EGFR (SEQ ID NO.: 11):

[0169] MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYD LSFLKTIQEVAGYVLIALNTVERI PLENLQI IRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQEILHGAVRF SNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGSCQKCDPSCPNGSCWGAGEENCQKLTKI ICAQQCSGRCRG KSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYV VTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVA FRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEI IRGRTKQHGQFSLAVVSLNITSLGL RSLKEISDGDVI ISGNKNLCYANTINWKKLFGTSGQKTKI ISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVS CRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVM GENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVR KRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWI PEGEKVKI PVAIKELREA TSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGM NYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSY GVTVWELMTFGSKPYDGI PASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELI IEFSKMARDP QRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLI PQQGFFSSPSTSRTPLLSSLSATSNNSTVACI DRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDPHY QDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPNGI FKGSTAENAEYLRV APQSSEFIGA

[0170] The tumor antigen, understood as the tumor antigen to be targeted by the “antibody moiety (a)” (l.e. an antibody and / or an antibody construct as defined herein), of the immunoconjugate of the present invention, may also be FR-a. Folate receptor 1 (Folate receptor alpha, F0LR1 or FR-a) is a protein that in humans is encoded by the FOLR1 gene. The protein encoded by this gene is a member of the folate receptor (FOLR) family. Members of this family have a high affinity for folic acid and for several reduced folic acid derivatives, and mediate delivery of 5-methy Itetrahyd rofolate to the interior of cells. This receptor is responsible for binding to folic acid and its derivatives, which becomes crucial during fetal development. By adding folate supplementation during pregnancy, neural tube defects in the fetus are prevented. Folate derivatives are necessary for important metabolic processes such as DNA, protein and lipid methylation. More importantly, folate plays a major role in DNA replication and cell division, which are common characteristics of rapid growth. Even though it is unclear how folate affects neural tube formation, scientists are certain that without appropriate folate levels, neural tube defects can develop through human and mice studies. Neural tube defects refer to the improper development of the neural tube by not being sealed correctly. This results in exencephaly or spina bifida, both nervous system abnormalities. This gene is composed of 7 exons; exons 1 through 4 encode the 5' UTR and exons 4 through 7 encode the open reading frame. Due to the presence of 2 promoters, multiple transcription start sites, and alternative splicing of exons, several transcript variants are derived from this gene. These variants differ in the lengths of 5' and 3' UTR, but they encode an identical amino acid sequence. FRa, due to its high expression in some tumors, is an attractive therapeutic target for the development of novel anti-cancer agents in order to limit toxic side-effects on off-target tissues. FR-a can be overexpressed by a number of epithelial-derived tumors including ovarian, breast, renal, lung, colorectal, and brain. According to a review published in 2020, elevated expression of FR-a was noted in mesotheliomas (72-100% of cases), triple-negative breast cancer (35-68% of cases) and epithelial ovarian cancer (76-89% of cases). The tumor antigen FR-a is characterized by an amino acid sequence according to SEQ ID NO.: 12.

[0171] FR-a (SEQ ID NO.: 12):

[0172] MAQRMTTQLLLLLVWVAVVGEAQTRIAWARTELLNVCMNAKHHKEKPGPEDKLHEQCRPWRKNACCSTNTSQEAH KDVSYLYRFNWNHCGEMAPACKRHFIQDTCLYECSPNLGPWIQQVDQSWRKERVLNVPLCKEDCEQWWEDCRTSY TCKSNWHKGWNWTSGFNKCAVGAACQPFHFYFPTPTVLCNEIWTHSYKVSNYSRGSGRCIQMWFDPAQGNPNEEV ARE YAAAM S GAG PWAAW P FLLS LALML LWLL S

[0173] The tumor antigen, understood as the tumor antigen to be targeted by the “antibody moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may also be MUC16. Mucin-16 (MUC16) also known as ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the MUC16 gene. MUC16 is a member of the mucin family glycoproteins. MUC16 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers, most notably ovarian cancer, or other conditions that are benign. The tumor antigen MUC16 is characterized by an amino acid sequence according to SEQ ID NO.: 13. MUC16 (SEQ ID NO.: 13):

[0174] MLKPSGLPGSSSPTRSLMTGSRSTKATPEMDSGLTGATLSPKTSTGAIVVTEHTLPFTSPDKTLASPTSSVVGRT

[0175] TQSLGVMSSALPESTSRGMTHSEQRTSPSLSPQVNGTPSRNYPATSMVSGLSSPRTRTSSTEGNFTKEASTYTLT

[0176] VETTSGPVTEKYTVPTETSTTEGDSTETPWDTRYI PVKITSPMKTFADSTASKENAPVSMTPAETTVTDSHTPGR

[0177] TNPSFGTLYSSFLDLSPKGTPNSRGETSLELILSTTGYPFSSPEPGSAGHSRI STSAPLSSSASVLDNKISETS I

[0178] FSGQSLTSPLSPGVPEARASTMPNSAI PFSMTLSNAETSAERVRSTISSLGTPSISTKQTAETILTFHAFAETMD

[0179] IPSTHIAKTLASEWLGSPGTLGGTSTSALTTTSPSTTLVSEETNTHHSTSGKETEGTLNTSMTPLETSAPGEESE

[0180] MTATLVPTLGFTTLDSKIRSPSQVSSSHPTRELRTTGSTSGRQSSSTAAHGSSDILRATTSSTSKASSWTSESTA

[0181] QQFSEPQHTQWVETSPSMKTERPPASTSVAAPITTSVPSVVSGFTTLKTSSTKGIWLEETSADTLIGESTAGPTT

[0182] HQFAVPTGI SMTGGSSTRGSQGTTHLLTRATASSETSADLTLATNGVPVSVSPAVSKTAAGSSPPGGTKPSYTMV

[0183] SSVI PETSSLQSSAFREGTSLGLTPLNTRHPFSSPEPDSAGHTKISTSI PLLSSASVLEDKVSATSTFSHHKATS

[0184] SITTGTPEISTKTKPSSAVLSSMTLSNAATSPERVRNATSPLTHPSPSGEETAGSVLTLSTSAETTDSPNIHPTG

[0185] TLTSESSESPSTLSLPSVSGVKTTFSSSTPSTHLFTSGEETEETSNPSVSQPETSVSRVRTTLASTSVPTPVFPT

[0186] MDTWPTRSAQFSSSHLVSELRATSSTSVTNSTGSALPKISHLTGTATMSQTNRDTFNDSAAPQSTTWPETSPRFK

[0187] TGLPSATTTVSTSATSLSATVMVSKFTSPATSSMEATSIREPSTTILTTETTNGPGSMAVASTNI PIGKGYITEG

[0188] RLDTSHLPIGTTASSETSMDFTMAKESVSMSVSPSQSMDAAGSSTPGRTSQFVDTFSDDVYHLTSREITIPRDGT

[0189] SSALTPQMTATHPPSPDPGSARSTWLGILSSSPSSPTPKVTMSSTFSTQRVTTSMIMDTVETSRWNMPNLPSTTS

[0190] LTPSNIPTSGAIGKSTLVPLDTPSPATSLEASEGGLPTLSTYPESTNTPSIHLGAHASSESPSTIKLTMASWKP

[0191] GSYTPLTFPSIETHIHVSTARMAYSSGSSPEMTAPGETNTGSTWDPTTYITTTDPKDTSSAQVSTPHSVRTLRTT

[0192] ENHPKTESATPAAYSGSPKISSSPNLTSPATKAWTITDTTEHSTQLHYTKLAEKSSGFETQSAPGPVSWIPTSP

[0193] TIGSSTLELTSDVPGEPLVLAPSEQTTITLPMATWLSTSLTEEMASTDLDISSPSSPMSTFAIFPPMSTPSHELS

[0194] KSEADTSAIRNTDSTTLDQHLGIRSLGRTGDLTTVPITPLTTTWTSVIEHSTQAQDTLSATMSPTHVTQSLKDQT

[0195] SIPASASPSHLTEVYPELGTQGRSSSEATTFWKPSTDTLSREIETGPTNIQSTPPMDNTTTGSSSSGVTLGIAHL

[0196] PIGTSSPAETSTNMALERRSSTATVSMAGTMGLLVTSAPGRSI SQSLGRVSSVLSESTTEGVTDSSKGSSPRLNT

[0197] QGNTALSSSLEPSYAEGSQMSTSIPLTSSPTTPDVEFIGGSTFWTKEVTTVMTSDISKSSARTESSSATLMSTAL

[0198] GSTENTGKEKLRTASMDLPSPTPSMEVTPWISLTLSNAPNTTDSLDLSHGVHTSSAGTLATDRSLNTGVTRASRL

[0199] ENGSDTSSKSLSMGNSTHTSMTYTEKSEVSSSIHPRPETSAPGAETTLTSTPGNRAISLTLPFSSIPVEEVISTG

[0200] ITSGPDINSAPMTHSPITPPTIVWTSTGTIEQSTQPLHAVSSEKVSVQTQSTPYVNSVAVSASPTHENSVSSGSS

[0201] TSSPYSSASLESLDSTI SRRNAITSWLWDLTTSLPTTTWPSTSLSEALSSGHSGVSNPSSTTTEFPLFSAASTSA

[0202] AKQRNPETETHGPQNTAASTLNTDASSVTGLSETPVGASISSEVPLPMAITSRSDVSGLTSESTANPSLGTASSA

[0203] GTKLTRTISLPTSESLVSFRMNKDPWTVSI PLGSHPTTNTETSIPVNSAGPPGLSTVASDVIDTPSDGAESIPTV

[0204] SFSPSPDTEVTTISHFPEKTTHSFRTISSLTHELTSRVTPI PGDWMSSAMSTKPTGASPSITLGERRTITSAAPT

[0205] TSPIVLTASFTETSTVSLDNETTVKTSDILDARKTNELPSDSSSSSDLINTSIASSTMDVTKTASISPTSISGMT

[0206] ASSS PSLFSSDRPQVPTSTTETNTATSPSVSSNTYSLDGGSNVGGTPSTLPPFTI THPVETSSALLAWSRPVRTF

[0207] STMVSTDTASGENPTSSNSVVTSVPAPGTWTSVGSTTDLPAMGFLKTSPAGEAHSLLASTIEPATAFTPHLSAAV

[0208] VTGSSATSEASLLTTSESKAIHSSPQTPTTPTSGANWETSATPESLLVVTETSDTTLTSKILVTDTILFSTVSTP

[0209] PSKFPSTGTLSGASFPTLLPDTPAIPLTATEPTSSLATSFDSTPLVTIASDSLGTVPETTLTMSETSNGDALVLK

[0210] TVSNPDRS I PGITIQGVTESPLHPSSTSPSKIVAPRNTTYEGSITVALSTLPAGTTGSLVFSQSSENSETTALVD

[0211] SSAGLERASVMPLTTGSQGMASSGGIRSGSTHSTGTKTFSSLPLTMNPGEVTAMSEITTNRLTATQSTAPKGI PV

[0212] KPTSAESGLLTPVSASSSPSKAFASLTTAPPTWGI PQSTLTFEFSEVPSLDTKSASLPTPGQSLNTIPDSDASTA SSSLSKSPEKNPRARMMTSTKAISASSFQSTGFTETPEGSASPSMAGHEPRVPTSGTGDPRYASESMSYPDPSKA

[0213] SSAMTSTSLASKLTTLFSTGQAARSGSSSSPISLSTEKETSFLSPTASTSRKTSLFLGPSMARQPNILVHLQTSA LTLSPTSTLNMSQEEPPELTSSQTIAEEEGTTAETQTLTFTPSETPTSLLPVSSPTEPTARRKSSPETWASSISV PAKTSLVETTDGTLVTTIKMSSQAAQGNSTWPAPAEETGSSPAGTSPGSPEMSTTLKIMSSKEPSISPEIRSTVR NSPWKTPETTVPMETTVEPVTLQSTALGSGSTSISHLPTGTTSPTKSPTENMLATERVSLSPSPPEAWTNLYSGT PGGTRQSLATMSSVSLESPTARSITGTGQQSSPELVSKTTGMEFSMWHGSTGGTTGDTHVSLSTSSNILEDPVTS PNSVSSLTDKSKHKTETWVSTTAI PSTVLNNKIMAAEQQTSRSVDEAYSSTSSWSDQTSGSDITLGASPDVTNTL YITSTAQTTSLVSLPSGDQGITSLTNPSGGKTSSASSVTSPSIGLETLRANVSAVKSDIAPTAGHLSQTSSPAEV SILDVTTAPTPGISTTITTMGTNSISTTTPNPEVGMSTMDSTPATERRTTSTEHPSTWSSTAASDSWTVTDMTSN LKVARSPGTISTMHTTSFLASSTELDSMSTPHGRITVIGTSLVTPSSDASAVKTETSTSERTLSPSDTTASTPIS TFSRVQRMSISVPDILSTSWTPSSTEAEDVPVSMVSTDHASTKTDPNTPLSTFLFDSLSTLDWDTGRSLSSATAT TSAPQGATTPQELTLETMISPATSQLPFSIGHITSAVTPAAMARSSGVTFSRPDPTSKKAEQTSTQLPTTTSAHP GQVPRSAATTLDVIPHTAKTPDATFQRQGQTALTTEARATSDSWNEKEKSTPSAPWITEMMNSVSEDTIKEVTSS SSVLRTLNTLDINLESGTTSSPSWKSSPYERIAPSESTTDKEAIHPSTNTVETTGWVTSSEHASHSTI PAHSASS KLTSPVVTTSTREQAIVSMSTTTWPESTRARTEPNSFLTIELRDVSPYMDTSSTTQTSI ISSPGSTAITKGPRTE ITSSKRISSSFLAQSMRSSDSPSEAITRLSNFPAMTESGGMILAMQTSPPGATSLSAPTLDTSATASWTGTPLAT TQRFTYSEKTTLFSKGPEDTSQPSPPSVEETSSSSSLVPIHATTSPSNILLTSQGHSPSSTPPVTSVFLSETSGL GKTTDMSRISLEPGTSLPPNLSSTAGEALSTYEASRDTKAIHHSADTAVTNMEATSSEYSPIPGHTKPSKATSPL VTSHIMGDITSSTSVFGSSETTEIETVSSVNQGLQERSTSQVASSATETSTVITHVSSGDATTHVTKTQATFSSG TSI SSPHQFITSTNTFTDVSTNPSTSLIMTESSGVTITTQTGPTGAATQGPYLLDTSTMPYLTETPLAVTPDFMQ SEKTTLISKGPKDVSWTSPPSVAETSYPSSLTPFLVTTIPPATSTLQGQHTSSPVSATSVLTSGLVKTTDMLNTS

[0214] MEPVTNSPQNLNNPSNEILATLAATTDIETIHPSINKAVTNMGTASSAHVLHSTLPVSSEPSTATSPMVPASSMG DALASI SIPGSETTDIEGEPTSSLTAGRKENSTLQEMNSTTESNI ILSNVSVGAITEATKMEVPSFDATFI PTPA QSTKFPDIFSVASSRLSNSPPMTISTHMTTTQTGSSGATSKIPLALDTSTLETSAGTPSVVTEGFAHSKITTAMN NDVKDVSQTNPPFQDEASSPSSQAPVLVTTLPSSVAFTPQWHSTSSPVSMSSVLTSSLVKTAGKVDTSLETVTSS PQSMSNTLDDISVTSAATTDIETTHPSINTVVTNVGTTGSAFESHSTVSAYPEPSKVTSPNVTTSTMEDTTISRS I PKSSKTTRTETETTSSLTPKLRETSISQEITSSTETSTVPYKELTGATTEVSRTDVTSSSSTSFPGPDQSTVSL DISTETNTRLSTSPIMTESAEITITTQTGPHGATSQDTFTMDPSNTTPQAGIHSAMTHGFSQLDVTTLMSRIPQD VSWTSPPSVDKTSSPSSFLSSPAMTTPSLI SSTLPEDKLSSPMTSLLTSGLVKITDILRTRLEPVTSSLPNFSST SDKILATSKDSKDTKEIFPSINTEETNVKANNSGHESHSPALADSETPKATTQMVITTTVGDPAPSTSMPVHGSS ETTNIKREPTYFLTPRLRETSTSQESSFPTDTSFLLSKVPTGTITEVSSTGVNSSSKISTPDHDKSTVPPDTFTG EIPRVFTSSIKTKSAEMTITTQASPPESASHSTLPLDTSTTLSQGGTHSTVTQGFPYSEVTTLMGMGPGNVSWMT TPPVEETSSVSSLMSSPAMTSPSPVSSTSPQSIPSSPLPVTALPTSVLVTTTDVLGTTSPESVTSSPPNLSSITH ERPATYKDTAHTEAAMHHSTNTAVTNVGTSGSGHKSQSSVLADSETSKATPLMSTTSTLGDTSVSTSTPNISQTN QIQTEPTASLSPRLRESSTSEKTSSTTETNTAFSYVPTGAITQASRTEI SSSRTSISDLDRPTIAPDISTGMITR LFTSPIMTKSAEMTVTTQTTTPGATSQGILPWDTSTTLFQGGTHSTVSQGFPHSEITTLRSRTPGDVSWMTTPPV EETSSGFSLMSPSMTSPSPVSSTSPESI PSSPLPVTALLTSVLVTTTNVLGTTSPEPVTSSPPNLSSPTQERLTT YKDTAHTEAMHASMHTNTAVANVGTSISGHESQSSVPADSHTSKATSPMGITFAMGDTSVSTSTPAFFETRIQTE STSSLIPGLRDTRTSEEINTVTETSTVLSEVPTTTTTEVSRTEVITSSRTTISGPDHSKMSPYISTETITRLSTF PFVTGSTEMAITNQTGPIGTISQATLTLDTSSTASWEGTHSPVTQRFPHSEETTTMSRSTKGVSWQSPPSVEETS SPSSPVPLPAITSHSSLYSAVSGSSPTSALPVTSLLTSGRRKTIDMLDTHSELVTSSLPSASSFSGEILTSEAST NTETIHFSENTAETNMGTTNSMHKLHSSVSIHSQPSGHTPPKVTGSMMEDAIVSTSTPGSPETKNVDRDSTSPLT

[0215] PELKEDSTALVMNSTTESNTVFSSVSLDAATEVSRAEVTYYDPTFMPASAQSTKSPDISPEASSSHSNSPPLTIS

[0216] THKTIATQTGPSGVTSLGQLTLDTSTIATSAGTPSARTQDFVDSETTSVMNNDLNDVLKTSPFSAEEANSLSSQA

[0217] PLLVTTSPSPVTSTLQEHSTSSLVSVTSVPTPTLAKITDMDTNLEPVTRSPQNLRNTLATSEATTDTHTMHPSIN

[0218] TAVANVGTTSSPNEFYFTVSPDSDPYKATSAVVITSTSGDSIVSTSMPRSSAMKKIESETTFSLIFRLRETSTSQ

[0219] KIGSSSDTSTVFDKAFTAATTEVSRTELTSSSRTSIQGTEKPTMSPDTSTRSVTMLSTFAGLTKSEERTIATQTG

[0220] PHRATSQGTLTWDTSITTSQAGTHSAMTHGFSQLDLSTLTSRVPEYISGTSPPSVEKTSSSSSLLSLPAITSPSP

[0221] VPTTLPESRPSSPVHLTSLPTSGLVKTTDMLASVASLPPNLGSTSHKIPTTSEDIKDTEKMYPSTNIAVTNVGTT

[0222] TSEKESYSSVPAYSEPPKVTSPMVTSFNIRDTIVSTSMPGSSEITRIEMESTFSLAHGLKGTSTSQDPIVSTEKS

[0223] AVLHKLTTGATETSRTEVASSRRTSIPGPDHSTESPDI STEVIPSLPISLGITESSNMTI ITRTGPPLGSTSQGT

[0224] FTLDTPTTSSRAGTHSMATQEFPHSEMTTVMNKDPEILSWTI PPSIEKTSFSSSLMPSPAMTSPPVSSTLPKTIH

[0225] TTPSPMTSLLTPSLVMTTDTLGTSPEPTTSSPPNLSSTSHEILTTDEDTTAIEAMHPSTSTAATNVETTSSGHGS

[0226] QSSVLADSEKTKATAPMDTTSTMGHTTVSTSMSVSSETTKIKRESTYSLTPGLRETSISQNASFSTDTSIVLSEV

[0227] PTGTTAEVSRTEVTSSGRTSI PGPSQSTVLPEISTRTMTRLFASPTMTESAEMTIPTQTGPSGSTSQDTLTLDTS

[0228] TTKSQAKTHSTLTQRFPHSEMTTLMSRGPGDMSWQSSPSLENPSSLPSLLSLPATTSPPPISSTLPVTISSSPLP

[0229] VTSLLTSSPVTTTDMLHTSPELVTSSPPKLSHTSDERLTTGKDTTNTEAVHPSTNTAASNVEIPSSGHESPSSAL

[0230] ADSETSKATSPMFITSTQEDTTVAISTPHFLETSRIQKESISSLSPKLRETGSSVETSSAIETSAVLSEVSIGAT

[0231] TEISRTEVTSSSRTSISGSAESTMLPEISTTRKI IKFPTSPILAESSEMTIKTQTSPPGSTSESTFTLDTSTTPS

[0232] LVITHSTMTQRLPHSEITTLVSRGAGDVPRPSSLPVEETSPPSSQLSLSAMISPSPVSSTLPASSHSSSASVTSL

[0233] LTPGQVKTTEVLDASAEPETSSPPSLSSTSVEILATSEVTTDTEKIHPFSNTAVTKVGTSSSGHESPSSVLPDSE

[0234] TTKATSAMGTISIMGDTSVSTLTPALSNTRKIQSEPASSLTTRLRETSTSEETSLATEANTVLSKVSTGATTEVS

[0235] RTEAISFSRTSMSGPEQSTMSQDISIGTIPRISASSVLTESAKMTITTQTGPSESTLESTLNLNTATTPSWVETH

[0236] SIVIQGFPHPEMTTSMGRGPGGVSWPSPPFVKETSPPSSPLSLPAVTSPHPVSTTFLAHIPPSPLPVTSLLTSGP

[0237] ATTTDILGTSTEPGTSSSSSLSTTSHERLTTYKDTAHTEAVHPSTNTGGTNVATTSSGYKSQSSVLADSSPMCTT

[0238] STMGDTSVLTSTPAFLETRRIQTELASSLTPGLRESSGSEGTSSGTKMSTVLSKVPTGATTEISKEDVTSI PGPA

[0239] QSTISPDISTRTVSWFSTSPVMTESAEITMNTHTSPLGATTQGTSTLDTSSTTSLTMTHSTISQGFSHSQMSTLM

[0240] RRGPEDVSWMSPPLLEKTRPSFSLMSSPATTSPSPVSSTLPESISSSPLPVTSLLTSGLAKTTDMLHKSSEPVTN

[0241] SPANLSSTSVEILATSEVTTDTEKTHPSSNRTVTDVGTSSSGHESTSFVLADSQTSKVTSPMVITSTMEDTSVST

[0242] STPGFFETSRIQTEPTSSLTLGLRKTSSSEGTSLATEMSTVLSGVPTGATAEVSRTEVTSSSRTSISGFAQLTVS

[0243] PETSTETITRLPTSSIMTESAEMMIKTQTDPPGSTPESTHTVDISTTPNWVETHSTVTQRFSHSEMTTLVSRSPG

[0244] DMLWPSQSSVEETSSASSLLSLPATTSPSPVSSTLVEDFPSASLPVTSLLNPGLVITTDRMGISREPGTSSTSNL

[0245] SSTSHERLTTLEDTVDTEDMQPSTHTAVTNVRTSISGHESQSSVLSDSETPKATSPMGTTYTMGETSVS I STSDF

[0246] FETSRIQIEPTSSLTSGLRETSSSERISSATEGSTVLSEVPSGATTEVSRTEVISSRGTSMSGPDQFTISPDIST

[0247] EAITRLSTSPIMTESAESAITIETGSPGATSEGTLTLDTSTTTFWSGTHSTASPGFSHSEMTTLMSRTPGDVPWP

[0248] SLPSVEEASSVSSSLSSPAMTSTSFFSTLPESISSSPHPVTALLTLGPVKTTDMLRTSSEPETSSPPNLSSTSAE

[0249] ILATSEVTKDREKIHPSSNTPVVNVGTVIYKHLSPSSVLADLVTTKPTSPMATTSTLGNTSVSTSTPAFPETMMT

[0250] QPTSSLTSGLREISTSQETSSATERSASLSGMPTGATTKVSRTEALSLGRTSTPGPAQSTI SPEI STETITRIST

[0251] PLTTTGSAEMTITPKTGHSGASSQGTFTLDTSSRASWPGTHSAATHRSPHSGMTTPMSRGPEDVSWPSRPSVEKT

[0252] SPPSSLVSLSAVTSPSPLYSTPSESSHSSPLRVTSLFTPVMMKTTDMLDTSLEPVTTSPPSMNITSDESLATSKA

[0253] TMETEAIQLSENTAVTQMGTISARQEFYSSYPGLPEPSKVTSPVVTSSTIKDIVSTTI PASSEITRIEMESTSTL

[0254] TPTPRETSTSQEIHSATKPSTVPYKALTSATIEDSMTQVMSSSRGPSPDQSTMSQDISTEVITRLSTSPIKTEST EMTITTQTGSPGATSRGTLTLDTSTTFMSGTHSTASQGFSHSQMTALMSRTPGDVPWLSHPSVEEASSASFSLSS PVMTSSSPVSSTLPDSIHSSSLPVTSLLTSGLVKTTELLGTSSEPETSSPPNLSSTSAEILAITEVTTDTEKLEM TNVVTSGYTHESPSSVLADSVTTKATSSMGITYPTGDTNVLTSTPAFSDTSRIQTKSKLSLTPGLMETSI SEETS SATEKSTVLSSVPTGATTEVSRTEAISSSRTSIPGPAQSTMSSDTSMETITRISTPLTRKESTDMAITPKTGPSG ATSQGTFTLDSSSTASWPGTHSATTQRFPQSVVTTPMSRGPEDVSWPSPLSVEKNSPPSSLVSSSSVTSPSPLYS TPSGSSHSSPVPVTSLFTSIMMKATDMLDASLEPETTSAPNMNITSDESLAASKATTETEAIHVFENTAASHVET TSATEELYSSSPGFSEPTKVISPVVTSSSIRDNMVSTTMPGSSGITRI EIESMSSLTPGLRETRTSQDITSSTET STVLYKMPSGATPEVSRTEVMPSSRTSIPGPAQSTMSLDISDEVVTRLSTSPIMTESAEITITTQTGYSLATSQV TLPLGTSMTFLSGTHSTMSQGLSHSEMTNLMSRGPESLSWTSPRFVETTRSSSSLTSLPLTTSLSPVSSTLLDSS PSSPLPVTSLILPGLVKTTEVLDTSSEPKTSSSPNLSSTSVEIPATSEIMTDTEKIHPSSNTAVAKVRTSSSVHE SHSSVLADSETTITI PSMGITSAVDDTTVFTSNPAFSETRRI PTEPTFSLTPGFRETSTSEETTSITETSAVLYG VPTSATTEVSMTEIMSSNRIHI PDSDQSTMSPDI ITEVITRLSSSSMMSESTQMTITTQKSSPGATAQSTLTLAT TTAPLARTHSTVPPRFLHSEMTTLMSRSPENPSWKSSLFVEKTSSSSSLLSLPVTTSPSVSSTLPQSI PSSSFSV TSLLTPGMVKTTDTSTEPGTSLSPNLSGTSVEILAASEVTTDTEKIHPSSSMAVTNVGTTSSGHELYSSVSIHSE PSKATYPVGTPSSMAETS ISTSMPANFETTGFEAEPFSHLTSGFRKTNMSLDTSSVTPTNTPSSPGSTHLLQSSK TDFTSSAKTSSPDWPPASQYTEIPVDI ITPFNASPSITESTGITSFPESRFTMSVTESTHHLSTDLLPSAETIST GTVMPSLSEAMTSFATTGVPRAISGSGSPFSRTESGPGDATLSTIAESLPSSTPVPFSSSTFTTTDSSTI PALHE ITSSSATPYRVDTSLGTESSTTEGRLVMVSTLDTSSQPGRTSSSPILDTRMTESVELGTVTSAYQVPSLSTRLTR TDGIMEHITKIPNEAAHRGTIRPVKGPQTSTSPASPKGLHTGGTKRMETTTTALKTTTTALKTTSRATLTTSVYT PTLGTLTPLNASMQMASTIPTEMMITTPYVFPDVPETTSSLATSLGAETSTALPRTTPSVFNRESETTASLVSRS GAERSPVIQTLDVSSSEPDTTASWVIHPAETIPTVSKTTPNFFHSELDTVSSTATSHGADVSSAI PTNISPSELD ALTPLVTISGTDTSTTFPTLTKSPHETETRTTWLTHPAETSSTI PRTIPNFSHHESDATPSIATSPGAETSSAIP IMTVSPGAEDLVTSQVTSSGTDRNMTIPTLTLSPGEPKTIASLVTHPEAQTSSAI PTSTISPAVSRLVTSMVTSL AAKTSTTNRALTNSPGEPATTVSLVTHPAQTSPTVPWTTSIFFHSKSDTTPSMTTSHGAESSSAVPTPTVSTEVP GWTPLVTSSRAVISTTIPILTLSPGEPETTPSMATSHGEEASSAIPTPTVSPGVPGVVTSLVTSSRAVTSTTI P ILTFSLGEPETTPSMATSHGTEAGSAVPTVLPEVPGMVTSLVASSRAVTSTTLPTLTLSPGEPETTPSMATSHGA EASSTVPTVSPEVPGVVTSLVTSSSGVNSTSI PTLILSPGELETTPSMATSHGAEASSAVPTPTVSPGVSGVVTP LVTSSRAVTSTTIPILTLSSSEPETTPSMATSHGVEASSAVLTVSPEVPGMVTSLVTSSRAVTSTTIPTLTISSD EPETTTSLVTHSEAKMI SAI PTLAVSPTVQGLVTSLVTSSGSETSAFSNLTVASSQPETIDSWVAHPGTEASSVV PTLTVSTGEPFTNISLVTHPAESSSTLPRTTSRFSHSELDTMPSTVTSPEAESSSAISTTISPGI PGVLTSLVTS SGRDISATFPTVPESPHESEATASWVTHPAVTSTTVPRTTPNYSHSEPDTTPSIATSPGAEATSDFPTITVSPDV PDMVTSQVTSSGTDTSITI PTLTLSSGEPETTTSFITYSETHTSSAIPTLPVSPGASKMLTSLVI SSGTDSTTTF PTLTETPYEPETTAIQLIHPAETNTMVPRTTPKFSHSKSDTTLPVAITSPGPEASSAVSTTTISPDMSDLVTSLV PSSGTDTSTTFPTLSETPYEPETTATWLTHPAETSTTVSGTIPNFSHRGSDTAPSMVTSPGVDTRSGVPTTTIPP SI PGVVTSQVTSSATDTSTAI PTLTPSPGEPETTASSATHPGTQTGFTVPIRTVPSSEPDTMASWVTHPPQTSTP VSRTTSSFSHSSPDATPVMATSPRTEASSAVLTTISPGAPEMVTSQITSSGAATSTTVPTLTHSPGMPETTALLS THPRTETSKTFPASTVFPQVSETTASLTIRPGAETSTALPTQTTSSLFTLLVTGTSRVDLSPTASPGVSAKTAPL STHPGTETSTMIPTSTLSLGLLETTGLLATSSSAETSTSTLTLTVSPAVSGLSSASITTDKPQTVTSWNTETSPS VTSVGPPEFSRTVTGTTMTLIPSEMPTPPKTSHGEGVSPTTILRTTMVEATNLATTGSSPTVAKTTTTFNTLAGS LFTPLTTPGMSTLASESVTSRTSYNHRSWISTTSSYNRRYWTPATSTPVTSTFSPGISTSSI PSSTAATVPFMVP FTLNFTITNLQYEEDMRHPGSRKFNATERELQGLLKPLFRNSSLEYLYSGCRLASLRPEKDSSATAVDAICTHRP DPEDLGLDRERLYWELSNLTNGIQELGPYTLDRNSLYVNGFTHRSSMPTTSTPGTSTVDVGTSGTPSSSPSPTTA GPLLMPFTLNFTITNLQYEEDMRRTGSRKFNTMESVLQGLLKPLFKNTSVGPLYSGCRLTLLRPEKDGAATGVDA ICTHRLDPKSPGLNREQLYWELSKLTNDIEELGPYTLDRNSLYVNGFTHQSSVSTTSTPGTSTVDLRTSGTPSSL SSPTIMAAGPLLVPFTLNFTITNLQYGEDMGHPGSRKFNTTERVLQGLLGPIFKNTSVGPLYSGCRLTSLRSEKD GAATGVDAICIHHLDPKSPGLNRERLYWELSQLTNGIKELGPYTLDRNSLYVNGFTHRTSVPTSSTPGTSTVDLG

[0255] TSGTPFSLPSPATAGPLLVLFTLNFTITNLKYEEDMHRPGSRKFNTTERVLQTLLGPMFKNTSVGLLYSGCRLTL LRSEKDGAATGVDAICTHRLDPKSPGVDREQLYWELSQLTNGIKELGPYTLDRNSLYVNGFTHWIPVPTSSTPGT

[0256] STVDLGSGTPSSLPSPTTAGPLLVPFTLNFTITNLKYEEDMHCPGSRKFNTTERVLQSLLGPMFKNTSVGPLYSG CRLTLLRSEKDGAATGVDAICTHRLDPKSPGVDREQLYWELSQLTNGIKELGPYTLDRNSLYVNGFTHQTSAPNT

[0257] STPGTSTVDLGTSGTPSSLPSPTSAGPLLVPFTLNFTITNLQYEEDMHHPGSRKFNTTERVLQGLLGPMFKNTSV GLLYSGCRLTLLRPEKNGAATGMDAICSHRLDPKSPGLNREQLYWELSQLTHGIKELGPYTLDRNSLYVNGFTHR

[0258] SSVAPTSTPGTSTVDLGTSGTPSSLPSPTTAVPLLVPFTLNFTITNLQYGEDMRHPGSRKFNTTERVLQGLLGPL FKNSSVGPLYSGCRLISLRSEKDGAATGVDAICTHHLNPQSPGLDREQLYWQLSQMTNGIKELGPYTLDRNSLYV NGFTHRSSGLTTSTPWTSTVDLGTSGTPS PVPSPTTTGPLLVPFTLNFTITNLQYEENMGHPGSRKFNITESVLQ

[0259] GLLKPLFKSTSVGPLYSGCRLTLLRPEKDGVATRVDAICTHRPDPKI PGLDRQQLYWELSQLTHSITELGPYTLD RDSLYVNGFTQRSSVPTTSTPGTFTVQPETSETPSSLPGPTATGPVLLPFTLNFTITNLQYEEDMRRPGSRKFNT TERVLQGLLMPLFKNTSVSSLYSGCRLTLLRPEKDGAATRVDAVCTHRPDPKSPGLDRERLYWKLSQLTHGITEL

[0260] GPYTLDRHSLYVNGFTHQSSMTTTRTPDTSTMHLATSRTPASLSGPMTASPLLVLFTINFTITNLRYEENMHHPG SRKFNTTERVLQGLLRPVFKNTSVGPLYSGCRLTLLRPKKDGAATKVDAICTYRPDPKSPGLDREQLYWELSQLT

[0261] HSITELGPYTLDRDSLYVNGFTQRSSVPTTSIPGTPTVDLGTSGTPVSKPGPSAASPLLVLFTLNFTITNLRYEE NMQHPGSRKFNTTERVLQGLLRSLFKSTSVGPLYSGCRLTLLRPEKDGTATGVDAICTHHPDPKSPRLDREQLYW

[0262] ELSQLTHNITELGPYALDNDSLFVNGFTHRSSVSTTSTPGTPTVYLGASKTPASI FGPSAASHLLILFTLNFTIT NLRYEENMWPGSRKFNTTERVLQGLLRPLFKNTSVGPLYSGCRLTLLRPEKDGEATGVDAICTHRPDPTGPGLDR

[0263] EQLYLELSQLTHS ITELGPYTLDRDSLYVNGFTHRSSVPTTSTGWSEEPFTLNFTINNLRYMADMGQPGSLKFN ITDNVMQHLLSPLFQRSSLGARYTGCRVIALRSVKNGAETRVDLLCTYLQPLSGPGLPIKQVFHELSQQTHGITR

[0264] LGPYSLDKDSLYLNGYNEPGPDEPPTTPKPATTFLPPLSEATTAMGYHLKTLTLNFTISNLQYSPDMGKGSATFN STEGVLQHLLRPLFQKSSMGPFYLGCQLISLRPEKDGAATGVDTTCTYHPDPVGPGLDIQQLYWELSQLTHGVTQ LGFYVLDRDSLFINGYAPQNLSIRGEYQINFHIVNWNLSNPDPTSSEYITLLRDIQDKVTTLYKGSQLHDTFRFC LVTNLTMDSVLVTVKALFSSNLDPSLVEQVFLDKTLNASFHWLGSTYQLVDIHVTEMESSVYQPTSSSSTQHFYL

[0265] NFTITNLPYSQDKAQPGTTNYQRNKRNIEDALNQLFRNSSIKSYFSDCQVSTFRSVPNRHHTGVDSLCNFSPLAR RVDRVAIYEEFLRMTRNGTQLQNFTLDRSSVLVDGYSPNRNEPLTGNSDLPFWAVILIGLAGLLGVITCLICGVL

[0266] VTTRRRKKEGEYNVQQQCPGYYQSHLDLEDLQ

[0267] The tumor antigen, understood as the tumor antigen to be targeted by the “antibody moiety (a)” (i.e. an antibody, an antibody fragment and / or an antibody construct as defined herein) of the immunoconjugate of the present invention, may aiso be STEAP1. Metalloreductase STEAP1 is an enzyme that in humans is encoded by the STEAP1 gene. This gene is predominantly expressed in prostate tissue, and is found to be upregulated in multiple cancer cell lines. The gene product is predicted to be a six-transmembrane protein, and was shown to be a cell surface antigen significantly expressed at cell-cell junctions. The tumor antigen STEAP16 is characterized by an amino acid sequence according to SEQ ID NO.: 14.

[0268] STEAP1 (SEQ ID NO.: 14):

[0269] MESRKDITNQEELWKMKPRRNLEEDDYLHKDTGETSMLKRPVLLHLHQTAHADEFDCPSELQHTQELFPQWHL.pl KIAAI IASLTFLYTLLREVIHPLATSHQQYFYKIPILVINKVLPMVSITLLALVYLPGVIAAIVQLHNGTKYKKF PHWLDKWMLTRKQFGLLSFFFAVLHAIYSLSYPMRRSYRYKLLNWAYQQVQQNKEDAWIEHDVWRMEIYVSLGIV GLAILALLAVTSIPSVSDSLTWREFHYIQSKLGIVSLLLGTIHALI FAWNKWIDIKQFVWYTPPTFMIAVFLPIV VLI FKSILFLPCLRKKILKIRHGWEDVTKINKTEICSQL

[0270] Preferably, the tumor antigen to be targeted by “moiety (a) of the inventive immunoconjugate(s) is selected from GD2, O-acetyl-GD2, B7-H3, GPC2, and ALK. These tumor antigens are of particular use in the context of the present invention since these antigens allow for targeting of cancer cells that depend on RBM39, and, in particular, of the neuroblastoma cells, as outlined in Table 1 , supra. More preferably, the tumor antigen is selected from GD2, O-acetyl-GD2, and B7-H3. Even more preferably, the tumor antigen is GD2, or O-acetyl-GD2 (such as 7-O-acetyl-GD2 or 9-O-acetyl-GD2). In a particularly preferred embodiment of the present invention , said tumor antigen is GD2.

[0271] Accordingly, as provided by the present invention particularly preferred is an antibody, an antibody fragment, an antibody construct and / or a / bindi ng moiety that specifically binds GD2 (see also explanations of surface tumor antigen “GD2" provided herein above). Exemplified herein in the appended, yet nonlimiting examples are full-length antibodies that bind to / target GD2 and that are comprised as “moiety (a)” in the immunoconjugates of the present invention.

[0272] However, the tumor and / or cancer antigen may also be any other tumor and / or cancer antigen that is expressed on a tumor cell. As explained above, the cancer antigen CD33 can also be targeted by the “moiety (a)” of the inventive immunoconjugate. This allows for targeting of the inventive immunoconjugates to, e.g., AML cells, which are also dependent on RBM39.

[0273] In light of the above and even further illustrated herein below (and exemplified in the appended examples) “moiety (a)’’ of inventive immunoconjugate(s) has the ability of binding to and / or targeting of a tumor antigen which is displayed / expressed on the surface of a cancer cell. This is not only the case for (full- length) antibodies, but also applies when antibody fragments or antibody constructs are applied as “moiety a” of the immunoconjugates of the present invention. Useful, but non-limiting, antibodies / antibody fragments / antibody constructs / binding moieties (i.e., molecules / constructs to be employed in context of “moiety (a)” of the immunoconjugates of the present invention) are provided and explained in the following.

[0274] In general, the term "antibody" is used herein in the broadest sense and is not limited to full-length antibodies, like full immunoglobulins, in particular IgGs, fully-human antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies, "heterologous antibody" etc.. The term “antibody” encompasses also in context of this invention, various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies. Useful antibody moieties but also binding moieties to be employed in context of the inventive immunoconjugate(s) may also comprise antibody constructs, like single-chain constructs, multispecific antibodies (e.g., bispecific antibodies), and the like, as long as they exhibit the desired antigen-binding activity, i.e., (in context of this invention) the activity of binding to and / or targeting of a tumor and / or a cancer antigen displayed / expressed on the surface of a tumor cell / cancer cell. Again, also "antibody fragments” and “antibody constructs” are also considered “antibody moieties” in context of this invention.

[0275] Unless explicitly indicated to the contrary, when discussing the antibody / antibody fragment / antibody moiety / binding moiety of “moiety (a)" of the inventive immunoconjugate(s) or the properties thereof, whenever a reference is made to such a(n) antibody / antibody fragment / antibody moiety / binding moiety, any form of the antibody / antibody moiety / binding moiety as apparent to the skilled person that binds to / targets a tumor and / or cancer antigen displayed on and / or expressed on the surface of a tumor cell and / or cancer cell is meant.

[0276] Accordingly, and as apparent to the skilled person, the term “antibody” is non-limiting and in certain cases the term “antibody” may also refer to an antigen-binding fragment of such an antibody. As preferably referred to herein, an "antigen-binding fragment" of an antibody refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’ -SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); single-domain antibodies (also known as nanobodies) and multispecific antibodies formed from, e.g., antibody fragments. Such "antigen-binding fragments" or “antibody fragments” may also considered in context of this invention as an “antibody moiety" that (specifically) binds to / targets a tumor and / or cancer antigen which is (preferably) displayed on and / or which is expressed on the surface of a cancer cell. Preferably, the antibody, as referred to herein as "moiety (a)" of the immunoconjugate of the present invention, is (but not limiting) a full-length antibody (like an immunoglobulin, e.g., an IgG) and not solely an antigen-binding fragment of the antibody. Yet, as explained above, nevertheless also "antigen-binding fragments" may be in context of this invention as an “binding / targeting moiety (a)” that (specifically) binds to / targets a tumor antigen which is displayed on and / or which is expressed on the surface of a cancer cell. The preferred "moiety (a)” of the immunoconjugate(s) of the present invention, may, accordingly be a monoclonal antibody, a chimeric antibody, a humanized antibody, a recombinant antibody, a bispecific antibody, a heterohybrid antibody, or a multi-specific antibody.

[0277] But also antibody constructs, like single chain antibodies, single-chain bispecific antibodies, multimeric antibodies, etc., can be employed as binding / targeting moieties to tumor and / or cancer antigens in the immunoconjugates / DACs of the present invention. Again, preferably, said tumor and / or cancer antigens displayed on and / or which are expressed on the surface of a tumor and / or cancer cell. Accordingly, also such antibody constructs, like bispecific antibodies, multi-specific antibodies, single chain antibodies, etc., may serve as “moiety (a)” of the inventive immunoconjugate(s) in context of this invention. These “moieties (a)” of the inventive immunoconjugate(s) have the ability of binding to and / or targeting of at least one tumor antigen which is displayed and / or expressed on the surface of a cancer cell / tumor cell.

[0278] The term "monoclonal antibody” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Monoclonal antibodies are advantageous in that they may be synthesized by a hybridoma culture, essentially uncontaminated by other immunoglobulins. The modified "monoclonal" indicates the character of the antibody as being amongst a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. The monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method described first by Kohler, Nature 256 (1975), 495.

[0279] The term “chimeric antibodies”, refers to an antibody which comprises a variable region of the present invention fused or chimerized with an antibody region (e.g., constant region) from another, human or nonhuman species (e.g., mouse, horse, rabbit, dog, cow, chicken). The term “recombinant antibody” includes all antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g. a mouse) that is transgenic for human immunoglobulin genes, antibodies expressed using a recombinant expression vector transfected into a host cell, antibodies isolated from a recombinant, combinatorial human antibody library, or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Accordingly, the term antibody also relates to recombinant human antibodies, heterologous antibodies and heterohybrid antibodies. Such recombinant human antibodies have variable and constant regions (if present) derived from human germline immunoglobulin sequences. Such antibodies can, however, be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0280] A "heterologous antibody" is defined in relation to the transgenic non-human organism producing such an antibody. This term refers to an antibody having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic non-human animal, and generally from a species other than that of the transgenic non-human animal.

[0281] The term "heterohybrid antibody" refers to an antibody having light and heavy chains of different organismal origins. For example, an antibody having a human heavy chain associated with a murine light chain is a heterohybrid antibody. Examples of heterohybrid antibodies include chimeric and humanized antibodies.

[0282] The term antibody also relates to humanized antibodies. "Humanized" forms of non-human (e.g. murine or rabbit) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Often, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibody may comprise residues, which are found neither in the recipient antibody nor in the imported CDR or framework sequences. These modifications are made to further refine and optimize antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see: Jones Nature 321 (1986), 522-525; Reichmann Nature 332 (1998), 323-327 and Presta Curr Op Struct Biol 2 (1992), 593-596.

[0283] Accordingly, in context of the present invention, the term "antibody” relates, inter alia, to full immunoglobulin molecules as well as to parts of such immunoglobulin molecules. Accordingly, the skilled person may also subsume antibody fragments and antibody constructs as referred to herein under the generic term “antibodies”. Yet, in a preferred embodiment of the immunoconjugates of the present invention, the “moiety (a)” comprises a (full-length) antibody as binding / targeting moiety. Exemplified in this context are herein: full-length antibodies that target / bind to GD2 (as tumor-associated antigen (TAAs)), like the chimeric mouse-human antibodies dinutuximab beta (ch14.18 / CHO, tradename Qarziba), dinutuximab (ch14.18, tradename Unituxin) or the humanized full-length IgG naxitamab (hu3F8, tradename Danyelza). Also exemplified in this context is humanized hu14.18K322A antibody (which is described, inter alia, in US 10,633,452 B2).

[0284] Again, and in context of the present invention, the ’’moiety (a)” of the inventive immunoconjugates must be capable / able to bind to the herein defined (surface) tumor / cancer antigen. Furthermore, the term "antibody” in context of “moiety (a)” may also relate, as discussed above, to modified and / or altered antibody molecules, antibody fragments and antibody constructs. Accordingly, in context of this invention, the term “antibody” also relates to recombinantly or synthetically generated / synthesized antibodies or antibody constructs. The terms “antibody” or “antibody fragments” in context of “moiety (a)” of the herein provided immunoconjugates also relate to antibodies / antibody constructs / antibody fragments that comprise at least one "antigen-binding fragment” or “antigen-binding part” of antibodies that target / bind to a (surface) antigen on tumor / cancer cells. Such an “antigen- binding part” may comprise, the CDR(s) of a corresponding antibody). Accordingly, “moiety (a) of the inventive immunoconjugates may also comprise antibody fragments like, separated light and heavy chains, Fab, Fv, Fab’, Fab’-SH or F(ab’)2. The term “antibody" also comprises but is not limited to fully-human antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies and, in certain embodiments also "antibody constructs”, like single chain Fvs (scFv) or antibody-fusion proteins. Yet, the term preferably (but not limiting) relates to intact antibodies in context of this invention.

[0285] A single chain antibody, i.e., “single-chain Fv” or “scFv” antibody fragments have, in the context of the invention, the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. Techniques described for the production of single chain antibodies are described, e.g., in Pluckthun in The Pharmacology of Monoclonal Antibodies, Rosenburg and Moore eds. Springer- Verlag, N.Y. (1994), 269- 315.

[0286] A “Fab fragment” as used herein is comprised of one light chain and the CH 1 and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0287] An "Fc" region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0288] A "Fab' fragment" contains one light chain and a portion of one heavy chain that contains the VH domain and the C H1 domain and also the region between the CH1 and C H2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab’ fragments to form a F(ab')2 molecule.

[0289] A "F(ab')2 fragment" contains two light chains and two heavy chains containing a portion of the constant region between the CH1 and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab')2 fragment thus is composed of two Fab’ fragments that are held together by a disulfide bond between the two heavy chains.

[0290] The "Fv region" comprises the variable regions from both the heavy and light chains, but lacks the constant regions. A bispecific antibody, as referred to herein, is an antibody that can simultaneously bind to two different types of antigen, or to two different epitopes of the same antigen. Upon development, bispecific antibodies can be manufactured in several structural formats, which are known to the skilled person.

[0291] A multi-specific antibody, as referred to herein, is an antibody that can simultaneously bind to more than two different types of antigen, or to more than two different epitopes of the same antigen.

[0292] Antibodies, antibody constructs, antibody fragments, antibody derivatives (all being Ig-derived) to be employed in accordance with the invention or their corresponding immunoglobulin chain(s) can be further modified using conventional techniques known in the art, for example, by using amino acid deletion(s), insertion(s), substitutlon(s), addition(s), and / or recombination(s) and / or any other modification(s) known In the art either alone or in combination. Methods for introducing such modifications in the DNA sequence underlying the amino acid sequence of an immunoglobulin chain are well known to the person skilled in the art; see, e.g., Sambrook (1989), loc. cit. The term “Ig-derived domain” particularly relates to (poly) peptide constructs comprising at least one CDR, Fragments or derivatives of the recited Ig-derived domains define (poly) peptides which are parts of the above antibody molecules and / or which are modified by chemical / biochemical or molecular biological methods. Corresponding methods are known in the art and described inter alia in laboratory manuals (see Sambrook et al., Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press, 2nd edition (1989) and 3rd edition (2001); Gerhardt et al., Methods for General and Molecular Bacteriology ASM Press (1994); Lefkovlts, Immunology Methods Manual: The Comprehensive Sourcebook of Techniques; Academic Press (1997); Golemis, Protein- Protein Interactions: A Molecular Cloning Manual Cold Spring Harbor Laboratory Press (2002)).

[0293] The antibody to be employed as “moiety (a)” of the immunoconjugate(s) may be a monoclonal antibody.

[0294] The antibody as referred to herein may be an IgG (like an lgG1 , lgG2a or lgG2b, lgG3, lgG4), IgM, lgA1 , lgA2, IgAsec, IgD, IgE. As used herein, "isotype" refers to the antibody class (e.g., IgM or IgG) that is encoded by heavy chain constant region genes. The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, lgA1 , and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, E, y, and p, respectively. Preferably, the (monoclonal) antibody to be employed in the inventive immunoconjugate is an lgG1 antibody (or in the IgG 1 format). However, also lgG4 antibodies are of clinical relevance and accordingly, “moiety (a)” of the inventive immunoconjugate(s) may also be an antibody that is of either (human) lgG1 or lgG4 format.

[0295] Accordingly, the antibodies to be employed as “moiety (a)” in the immunoconjugates of the present invention may be full-length or can include only an antigen-binding fragment such as the antibody constant and / or variable domain of IgG 1 , lgG2, lgG3, lgG4, IgM, Ig A1 , lgA2, IgAsec, IgD or IgE. “Moiety (a)” in the immunoconjugates of the present invention may be an antibody fragment, and accordingly, said “moiety (a)” may also comprise of, e.g., a Fab fragment, a F(ab')2 fragment or a Fv fragment of such full-length antibodies.

[0296] Selection of a particular antibody for “moiety (a)” of the inventive immunoconjugate(s) depends on particular cancer cell / tumor cell to be targeted and the particular cell surface tumor / cancer antigen to be targeted. In the case of high-risk neuroblastoma as exemplified herein, the moiety (a)" of the inventive immunoconjugate(s) is a full-length IgG monoclonal antibody (mAb) or antibody fragment targeting GD2, B7-H3 (CD276), GPC2 or ALK (CD246). GD2, B7-H3 (CD276), GPC2 and ALK (CD246) are well- established neuroblastoma tumor-associated antigens (TAAs) and have previously been used as cell surface targets for the development of ADCs for the targeted therapy of neuroblastoma.10-16

[0297] In addition to the abovementioned tumor-associated antigens (TAAs) as well as cancer-associated antigens (CAAs) and for targeting other tumor and or cancer types, additional targets for the “moiety (a)” of the inventive immunoconjugate(s) may include: HER2 and Trop-2 for targeting breast cancer cells; HER3 for targeting melanoma cancer cells; CD33, CLL-1 (CD371), c-KIT (CD117) or CD123 for targeting AML cancer cells; EGFR, or MUC16 for targeting colorectal cancer cells, FR-a or Trop-2 for targeting ovarian cancer cells and STEAP-1 for targeting Ewing sarcoma cancer cells. Furthermore, additional targets for targeting medulloblastoma cells, in addition to GD2, include B7-H3 and GPC2, additional targets for targeting glioma cells, besides GD2, include B7-H3 and Trop-2. In this context, see also Table 1 , supra.

[0298] In context of this invention, it was surprisingly found that immunoconjugates targeting via its “moiety (a)”, (for example via its antibody-binding moiety) tumor antigen(s) / cancer antigen(s) on cancer and / or tumor cells, are of particular and unexpected high potency when the immunoconjugate comprises as "moiety (b)” the compound according to formula (I) as described herein above. Said “moiety (b) is also considered as the “payload” in context of this Invention. The compound of formula (I) is able to function as a degrader of the RBM39 oncoprotein.

[0299] The present invention is of particular advantage in tumors / cancer cells that display GD2 on their surface. However, as is evident for the person skilled in the art, the payload of the present invention as well as herein disclosed linkers and linker structure (like in particular specific linkers as disclosed herein, including but not limiting to the linker structures as defined, e.g., in formula (II) herein) are particularly suitable in the medical means and methods provided herein. The person skilled in the art is readily in the position to find targeting antibodies, antibody fragments, antibody molecules, antibody moieties / antibody constructs / binding moieties that comprise antigen-binding parts or fragments of such target-binding which can be used In the contest of the present invention as “moiety (a)” of the inventive immunoconjugates. The immunoconjugates, i.e., can be loaded with the payload(s) provided herein. This payload Is or is comprised in “moiety (b)” of the inventive immunoconjugate(s).

[0300] For example, useful targeting moieties (i.e. “moiety (a)” in the inventive immunoconjugates) may comprise as a non-limiting, yet preferred embodiment a full-length IgG mAb targeting GD2 (as tumor-associated antigen (TAAs)). This antibody can be a chimeric mouse-human antibody, like dinutuximab beta (ch14.18 / CHO, tradename Qarziba) or dinutuximab (ch14.18, tradename Unituxin). It can also be a humanized full-length IgG, like e.g., naxitamab (hu3F8, tradename Danyelza) or humanized hu14.18K322A antibody (which is described, inter alia, in US 10,633,452 B2). Preferably, in the immunoconjugate of the present invention, “moiety (a)”, I.e., the antibody / binding moiety binding to a tumor antigen displayed on the surface of a cancer cell, may be dinutuximab beta, dinutuximab or naxitamab. The experimental part provided below shows corresponding, unexpected results and evidence that in particular these antibodies are useful in the herein claimed immunoconjugates as “moiety (a)”.

[0301] As mentioned above, the present invention is not restricted to the use of (full-length) antibody as “moiety (a)” in the Inventive immunoconjugates. For example, also antibody fragments or antibody constructs may be employed.

[0302] Such antibody fragments or antibody constructs may (and preferably do) comprise parts of antibodies that bind to the desired target. Accordingly, and is evident for the skilled person, "moiety (a)” of the inventive immunoconjugates may also comprise, e.g., antibody fragments or antibody constructs that comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs of a given “targeting” or “binding” antibody. Herein below, certain useful CDRs of illustrative antibodies are also provided. Examples of useful “antibody fragments” and “antibody constructs” in context of this invention are provided herein.

[0303] Similarly, “moiety (a)” of the inventive immunoconjugate(s) may also comprise the variable regions of these “targeting” / ”binding" antibodies that target / bind to a (surface) antigen on cancer / tumor cells. Illustrative examples of such variable light chain regions (VL) as well as variable heavy chain regions (VH) are also provided herein. Such variable regions of these “targetingV’binding” antibodies, and / or CDRs of these “targetingV’binding” antibodies may also be comprised in useful antibody fragments and / or antibody constructs as employed in “moiety (a)" of the inventive immunoconjugates.

[0304] In the following, specific sequences and sequence information of antibodies and of antibody parts (like CDRs and variable regions (VH / VL regions) useful in context of the immunoconjugates of the present invention are provided. Accordingly, this information comprises, inter alia, sequences of full-length heavy chain (HC) and / or light chain (LC) sequences, as well as corresponding variable regions and CDRs. It is evident for the skilled person that the full-length heavy chain (HC) and / or light chain (LC) sequences (as well as the herein above recited variable regions of the heavy and / or the light chains) may comprise modifications to the these provided sequences. Also, such modified sequences do not deviate from the gist of the present invention. Such modifications may comprise, inter alia, amino acid exchanges, additions and / or deletions. Preferably, when such modifications are introduced in such full-length heavy chain (HC) and / or in these light chain (LC) sequences or the variable regions of the heavy and / or the light chain, the comprised CDRs remain stable and correspond to the CDRs as recited herein for the corresponding antibody. However, it is also envisaged that the CDRs in such sequences may comprise certain modifications / mutations etc. However, were this the case, in context of this invention the antibody / antibody construct comprised as “moiety (a)” still needs to bind to the tumor / cancer antigen to be targeted by the herein described inventive immunoconjugates.

[0305] According to the present invention, “moiety (a)” of the inventive immunoconjugate(s) may be or may comprise the antibodies dinutuximab beta or dinutuximab (both chimeric, full-length anti-GD2 antibodies). These both antibodies / antibody constructs are characterized by the same sequence, as outlined in the following. Dinutuximab (ch14.18) or Dinutuximab beta (ch14.18 / CHO) (chimeric anti-GD2) heavy chain (SEQ ID NO.: 15):

[0306] EVQLLQSGPELEKPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRATLTVDKS SSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0307] Dinutuximab or Dinutuximab beta (chimeric anti-GD2) light chain (SEQ ID NO.: 16):

[0308] EIVMTQSPATLSVSPGERATLSCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFSGSGSGTD FTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0309] Accordingly, “moiety (a)" of the inventive immunoconjugate may be or may comprise an antibody, and antibody fragment and / or an antibody construct comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence GSSFTGYN (SEQ ID NO.: 29), a CDR-H2 having the amino acid sequence IDPYYGGT (SEQ ID NO.: 30), and a CDR-H3 having the amino acid sequence VSGMEY (SEQ ID NO.: 31), and a light chain variable region comprising a CDR-L1 having the amino acid sequence QSLVHRNGNTY (SEQ ID NO.: 32), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence QSTHVPPLT (SEQ ID NO.: 33). Said antibody / antibody construct may comprise a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0310] EVQLLQSGPELEKPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRA TLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS (SEQ ID NO.: 34), and / or a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence: EIVMTQSPATLSVSPGERATLSCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFS GSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK (SEQ ID NO.: 35).

[0311] Said antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate(s) comprises or may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 15) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 16). Yet, as mentioned above, these sequences may also comprise certain modifications without deviating from the gist of the present invention.

[0312] It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as "moiety (a)” of the herein described immunoconjugate(s).

[0313] As further provided by the present invention, “moiety (a)” of the inventive immunoconjugates may be or may comprise naxitamab (humanized 3F8 anti-GD2, hu3F8), characterized by the sequence as outlined in the following.

[0314] Naxitamab (humanized 3F8 anti-GD2) heavy chain (SEQ ID NO.: 17):

[0315] QVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYNSAFMSRLTISKDNSK NTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0316] Naxitamab (humanized 3F8 anti-GD2) light chain (SEQ ID NO.: 18):

[0317] EIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPARFSGSGYGTEFTFTI SSVQSEDFAVYFCQQDYSSFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0318] Accordingly, “moiety (a)” of the inventive immunoconjugate may be or may comprise an antibody, and antibody fragment and / or an antibody construct comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence NYGVH (SEQ ID NO.: 36), a CDR-H2 having the amino acid sequence VIWAGGITNYNSAFM (SEQ ID NO.: 37), and a CDR-H3 having the amino acid sequence RGGHYGYALDY (SEQ ID NO.: 38), and a light chain variable region comprising a CDR-L1 having the amino acid sequence KASQSVSNDVT (SEQ ID NO.: 39), a CDR-L2 having the amino acid sequence SASNRYS (SEQ ID NO.: 40), and a CDR-L3 having the amino acid sequence QQDYSSF (SEQ ID NO.: 41). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0319] QVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYNSAFMSRL TISKDNSKNTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSS (SEQ ID NO.: 42), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0320] EIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPARFSGSGYG TEFTFTISSVQSEDFAVYFCQQDYSSFGQGTKLEIK (SEQ ID NO.: 43).

[0321] It is preferred that said antibody comprises or may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 17) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 18). Yet, as mentioned above, these sequences may also comprise certain modifications without deviating from the gist of the present invention.

[0322] Said antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 17) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 18). It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deferring from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above, Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as "moiety (a)” of the herein described immunoconjugate(s).

[0323] As further provided by the present invention, “moiety (a)” of the inventive immunoconjugates may be or may comprise hu14.18K322A (humanized anti-GD2) characterized by the sequence as outlined in the following. hu14.18K322A (humanized anti-GD2) heavy chain (SEQ ID NO.: 26):

[0324] EVQLVQSGAEVEKPGASVKISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRATLTVDKS TSTAYMHLKSLRSEDTAVYYCVSGMEYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPV TVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCAVSNAALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAV EWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK hu14.18K322A (humanized anti-GD2) light chain (SEQ ID NO.: 27):

[0325] DVVMTQTPLSLPVTPGEPASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFSGSGSGTD FTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0326] As provided by the present invention, “moiety (a)” may also be an antibody, and antibody fragment and / or an antibody construct comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence GSSFTGYN (SEQ ID NO.: 44), a CDR-H2 having the amino acid sequence IDPYYGGT (SEQ ID NO.: 45), and a CDR-H3 having the amino acid sequence VSGMEY (SEQ ID NO.: 46), and a light chain variable region comprising a CDR-L1 having the amino acid sequence QSLVHRNGNTY (SEQ ID NO.: 47), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence QSTHVPPLT (SEQ ID NO.: 48). Said antibody comprises or may comprise a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0327] EVQLVQSGAEVEKPGASVKISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRA TLTVDKSTSTAYMHLKSLRSEDTAVYYCVSGMEYWGQGTSVTVSS (SEQ ID NO.: 49), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0328] DVVMTQTPLSLPVTPGEPASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFS GSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK (SEQ ID NO.: 50).

[0329] Accordingly, the antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 49) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 50). It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deferring from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as “moiety (a)” of the herein described immunoconjugate(s).

[0330] Said antibody comprises or may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 26) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 27). Yet, as mentioned above, these sequences may also comprise certain modifications without deferring from the gist of the present invention.

[0331] Again, said antibody / antibody construct (etc.) of "moiety (a)” of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 26) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 27). It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deferring from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as “moiety (a)” of the herein described immunoconjugate(s). In order to enhance neuroblastoma tumor cell-specificity and reduce unwanted neurotoxicity, full-length IgG mAb can be a chimeric mouse-human C.8B6 antibody targeting O-acetyl-GD2 ganglioside (OAcGD2) TAA. Studies have shown that (neuroblastoma) tumor cells that express GD2 also express its O-acetyl derivative OAcGD2 and it was also found that OAcGD2 is not expressed by peripheral nerve fibers. The absence of OAcGD2 on nerve fibers leads to the reduction of adverse neurological side effects compared to the anti-GD2 antibody-based immunotherapy with preserved high anti-GD2 activity. Antibody C.8B6 is, inter alia, disclosed in document EP 3 068 802 B1 .

[0332] Thus, according to the present invention, “moiety (a)” of the inventive immunoconjugate may be or may comprise a c.8B6 antibody, characterized by the sequence as outlined in the following: c.8B6 heavy chain (SEQ ID NO.: 22):

[0333] EVKLVESGGGLVLPGDSLRLSCATSEFTFTDYYMTWVRQPPRKALEWLGFIRNRANGYTTEYNPSVKGRFTISRD NSQSILYLQMNTLRTEDSATYYCARVSNWAFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK c.8B6 light chain (SEQ ID NO.: 23): DVVMTQTPLSLPVSLGDQASISCRSSQSLLKNNGNTFLHWYLQKSGQSPKLLIYKVSNRLSGVPDRFSGSGSGTY FTLKISRVEAEDLGVYFCSQSTHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0334] Accordingly, as provided herein, “moiety (a)” of the immunoconjugate of the present invention may be an antibody / antibody construct (etc.) which comprises a heavy chain variable region comprising a CDR-H1 having the amino acid sequence EFTFTDYY (SEQ ID NO.: 51), a CDR-H2 having the amino acid sequence IRNRANGYTT (SEQ ID NO.: 52), and a CDR-H3 having the amino acid sequence ARVSNWAFDY (SEQ ID NO.: 53), and a light chain variable region comprising a CDR-L1 having the amino acid sequence QSLLKNNGNTFL (SEQ ID NO.: 54), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence SQSTHIPYT (SEQ ID NO.: 55). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0335] EVKLVESGGGLVLPGDSLRLSCATSEFTFTDYYMTWVRQPPRKALEWLGFIRNRANGYTTEYNPSVKG

[0336] RFTISRDNSQSILYLQMNTLRTEDSATYYCARVSNWAFDYWGQGTTLTVSS (SEQ ID NO.: 56), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0337] DVVMTQTPLSLPVSLGDQASISCRSSQSLLKNNGNTFLHWYLQKSGQSPKLLIYKVSNRLSGVPDRFSG SGSGTYFTLKISRVEAEDLGVYFCSQSTHIPYTFGGGTKLEIK (SEQ ID NO.: 57).

[0338] Said antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 56) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 57). It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deferring from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as “moiety (a)” of the herein described immunoconjugate(s).

[0339] Said antibody / antibody construct (etc.) in “moiety (a)” of the immunoconjugate of the present invention may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 22) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 23).

[0340] Said antibody / antibody construct (etc.) of “moiety (a)" of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 22) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 23). It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deferring from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as “moiety (a)” of the herein described immunoconjugate(s).

[0341] Additionally, to further enhance neuroblastoma tumor cell-specificity and reduce unwanted neurotoxicity in the immunoconjugates of the present invention, the “moiety (a)” may be or may comprise, full-length IgG mAb that is a bispecific antibody that targets a combination of two TAA- GD2 and B7-H3 (SNIPER genetically engineered bispecific Abs, Paul Sondel, Invenra). B7-H3 is overexpressed on the surface of multiple tumor cells, with only minimal expression on the healthy tissue and absent on nerve cells.

[0342] ’’Moiety (a)” in the immunoconjugate of the present invention may also be (or may be derived from) Nivatrotamab (hu3F8-BsAb), a humanized anti-GD2 / CD3 bispecific (lgG(L)-scFv2) antibody. Nivatrotamab was in Phase l / ll clinical development for the treatment of relapsed / refractory neuroblastoma, osteosarcoma and other GD2+solid tumors- NCT03860207 (terminated) and relapsed / recurrent metastatic SCLC- NCT04750239 (terminated).

[0343] As understood herein, Nivatrotomab is characterized by the sequence as outlined in the following: Nivatrotamab Heavy chain (SEQ ID NO.: 24):

[0344] QVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYNSAFMSRLTI SKDNSK NTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAS TYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0345] Nivatrotamab Light chain fused to CD3-specific scFv via (G4S)3 linker (SEQ ID NO.: 25): EIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPARFSGSGYGTEFTFTI SSVQSEDFAVYFCQQDYSSFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECTSGGGGSGGGGSGG GGSQVQLVQSGGGVVQPGRSLRLSCKASGYTFTRYTMHWVRQAPGKCLEWIGYINPSRGYTNYNQKFKDRFTISR DNSKNTAFLQMDSLRPEDTGVYFCARYYDDHYSLDYWGQGTPVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGG GSDIQMTQSPSSLSASVGDRVTITCSASSSVSYMNWYQQTPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFT ISSLQPEDIATYYCQQWSSNPFTFGCGTKLQITR Accordingly, ’’moiety (a)” of the inventive immunoconjugate may be or may comprise a bispecific an antibody comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence NYGVH (SEQ ID NO.: 36), a CDR-H2 having the amino acid sequence VIWAGGITNYNSAFM (SEQ ID NO.: 37), and a CDR-H3 having the amino acid sequence RGGHYGYALDY (SEQ ID NO.: 38), and a light chain variable region comprising a CDR-L1 having the amino acid sequence KASQSVSNDVT (SEQ ID NO.: 39), a CDR-L2 having the amino acid sequence SASNRYS (SEQ ID NO.: 40), and a CDR-L3 having the amino acid sequence QQDYSSF (SEQ ID NO.: 41). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0346] QVQLVESGPGVVQPGRSLRISCAVSGFSVTNYGVHWVRQPPGKGLEWLGVIWAGGITNYNSAFMSRL TISKDNSKNTVYLQMNSLRAEDTAMYYCASRGGHYGYALDYWGQGTLVTVSS (SEQ ID NO.: 42), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0347] EIVMTQTPATLSVSAGERVTITCKASQSVSNDVTWYQQKPGQAPRLLIYSASNRYSGVPARFSGSGYG TEFTFTISSVQSEDFAVYFCQQDYSSFGQGTKLEIK (SEQ ID NO.: 43).

[0348] It is particularly preferred that said antibody comprises a heavy chain (HC) having the amino acid sequence (SEQ ID NO.: 24) and a light chain (LC) having the amino acid sequence (SEQ ID NO.: 25).

[0349] Said antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 42) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 43). It is evident for the skilled artisan that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deferring from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as “moiety (a)” of the herein described immunoconjugate(s).

[0350] In addition, to further enhance the efficacy of the anti-GD2 antibody-based therapy, full-length IgG mAb is a bispecific trifunctional antibody that targets a combination of GD2 and CD3 antigens (EKTOMUN, Trion Research). Such antibody can in addition to Fc-mediated cytotoxicity exert neuroblastoma cell killing by redirecting T cells towards GD2+neuroblastoma tumors via its CD3 binding arm.

[0351] Thus, accordingly, in one embodiment, ’’moiety (a)” of the inventive immunoconjugate(s) may also be or may comprise a bispecific antibody or antibody construct, which further binds to B7-H3 or to CD3. Preferably, (a) is a bispecific antibody or antibody construct, which further binds to B7-H3. Such exemplary antibodies include INV721 (which is described in US 2023 / 0018670 A1) or its afucosylated form INV724, and EKTOMUN (which is described in WO 2023 / 280880), which is a trifunctional antibody composed of a combination of mouse anti-GD2 lgG2a Me361 and rat anti-CD3 lgG2b 26II6 antibodies and produced using quadroma technology (see, e.g., Lindhofer H, Mocikat R, Steipe B, Thierfelder S. Preferential species restricted heavy / light chain pairing in rat / mouse quadromas: implications for a single-step purification of bispecific antibodies. J Immunol 1995;155:219-25)

[0352] In one embodiment of the immunoconjugate of the present invention, the antibody / antibody fragment / antibody construct (etc.) that is employed in the immunoconjugates of the inventions in “moiety (a)” is characterized by a point mutation K322A (in the Fc region).

[0353] In one embodiment of the immunoconjugate of the present invention, the antibody / antibody construct (etc.) that is employed in the immunoconjugates of the inventions in “moiety (a)" is a deglycosylated antibody / antibody moiety.

[0354] Another strategy for reducing the neuropathic pain which is likely mediated by antibody-dependent cell- mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) is via the decrease of antibody effector functions through Fc region engineering.

[0355] For example, hu14.18K332A is a humanized anti-GD2 mAb with a single point mutation K322A significantly reduces the CDC effector functions and induces less pain (based on opioid requirements) than dinutuximab (ch14.18) non-engineered antibody. Moreover, hu 14.18K332A was produced in a YB2 / 0 rat myeloma cell line with decreased fucosylation activity and it has been previously shown that reduction of fucose content within the glycosylation site of antibody Fc domain results in higher mAb binding affinity for CD16 (FcyRIII) on NK cells and subsequent increase in ADCC activity. it is noted that dinutuximab beta (ch14.18 / CHO, tradename Qarziba) is expressed in a recombinant DHFR-deficient CHO cell line with preserved fucosylation activity. Dinutuximab beta triggers CDC resulting in activation of the complement cascade and lysis of target cells which is implicated in the pain toxicity associated with anti-GD2 mAb immunotherapy.

[0356] According to the present invention, the (surface) cancer antigen may also be CD33. Thus, ’’moiety (a)” may be or may comprise an antibody / antibody construct (etc.) that specifically binds CD33. Preferably, such antibody in (a) that binds specifically CD33 is gemtuzumab, which is further defined in the following. ’’Moiety (a)” may be an antibody comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence GYTITDSNIH (SEQ ID NO.: 58), a CDR-H2 having the amino acid sequence YIYPYNGGTDYNQKFKN (SEQ ID NO.: 59), and a CDR-H3 having the amino acid sequence GNPWLAY (SEQ ID NO.: 60), and a light chain variable region comprising a CDR-L1 having the amino acid sequence RASESLDNYGIRFLT (SEQ ID NO.: 61), a CDR-L2 having the amino acid sequence AASNQGS (SEQ ID NO.: 62), and a CDR-L3 having the amino acid sequence QQTKEVPWS (SEQ ID NO.: 63). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0357] EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDYNQKFKNRA TLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVTVSS (SEQ ID NO.: 64), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence: DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQGSGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVK (SEQ ID NO.: 65).

[0358] It is particularly preferred that said antibody / antibody construct of “moiety (a)” comprises a heavy chain (HC) having the amino acid sequence:

[0359] EVQLVQSGAEVKKPGSSVKVSCKASGYTITDSNIHWVRQAPGQSLEWIGYIYPYNGGTDYNQKFKNRA TLTVDNPTNTAYMELSSLRSEDTAFYYCVNGNPWLAYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSE STAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKP SNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNW YVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPRE PQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO.: 66) and a light chain (LC) having the amino acid sequence:

[0360] DIQLTQSPSTLSASVGDRVTITCRASESLDNYGIRFLTWFQQKPGKAPKLLMYAASNQGSGVPSRFSGS GSGTEFTLTISSLQPDDFATYYCQQTKEVPWSFGQGTKVEVKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SPVTKSFNRGEC (SEQ ID NO.: 67).

[0361] Said antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate(s) may comprise a heavy chain (HC) having the amino acid sequence according to (SEQ ID NO.: 66) and a light chain (LC) having the amino acid sequence according to (SEQ ID NO.: 67). It is evident that also heavy and light chains (or variable regions of these heavy and / or light chains) that are homologous to these specific sequences can be employed in context of this invention, without deviating from the gist of the present invention. Preferably, these homologous sequences comprise at least one, at least two, at least three, at least four, at least five or all 6 CDRs as shown herein above. Accordingly, also antibody fragments or antibody constructs can be employed in context of this invention as “moiety (a)” of the herein described immunoconjugate(s).

[0362] In certain embodiments, antibody variants having one or more amino acid substitutions are provided that may be employed as antibody / antibody construct (etc.) of “moiety (a)” in the inventive immunoconjugate(s). Sites of interest for substitutional mutagenesis include the CDRs and FRs. Conservative substitutions are shown in Table D1 under the heading of "preferred substitutions." More substantial changes are provided in Table D1 under the heading of "exemplary substitutions," and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

[0363] Table D1. Amino acids may be grouped according to common side-chain properties:

[0364] (1) hydrophobic: Norleucine, Met, Ala, Vai, Leu, He;

[0365] (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu;

[0366] (4) basic: His, Lys, Arg;

[0367] (5) residues that influence chain orientation: Gly, Pro;

[0368] (6) aromatic: Trp, Tyr, Phe.

[0369] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0370] In certain embodiments, an antibody / antibody construct (etc.) of “moiety (a)” in the inventive immunoconjugate(s may be altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0371] Where the antibody / antibody construct (etc.) of “moiety (a)” in the inventive immunoconjugate(s) comprise an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26- 32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, W-acetyl glucosamine (GIcNAc), galactose, and sialic acid, as well as a fucose attached to a GIcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.

[0372] In one embodiment, antibody variants (to be employed as antibody / antibody construct (etc.) of “moiety (a)” in the inventive immunoconjugate(s)) are provided herein. Such antibody variants may have a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1 % to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e. g. complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fe region residues); however, Asn297 may also be located about + 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003 / 0157108 (Presta, L.); US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to "defucosylated" or "fucose deficient" antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US 2004 / 0093621 ; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; W02002 / 031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Pat Appl No US 2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1 ,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003 / 085 107).

[0373] Antibodies variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GIcNAc. Such antibody variants may have reduced fucosylation and / or Improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003 / 011878 (Jean-Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005 / 0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0374] In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human lgG1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.

[0375] In certain embodiments, the invention contemplates an antibody variant to be employed as antibody / antibody construct (etc.) of “moiety (a)” in the inventive immunoconjugate(s) that possesses some but not all effector functions, which make it a desirable candidate for applications in which the halflife of the antibody in vivo is important yet certain effector functions (such as complement and antibodydependent cellular cytotoxicity) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC (complement-dependent cytotoxicity) and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII and Fc(RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U.S. Patent No. 5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Natl Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Natl Acad. Sei. USA 82:1499- 1502 (1985); 5,821 ,337 (see Bruggemann, M, et al., J. Exp. Med. 166:1351-1361 (1987)).

[0376] Accordingly and preferably, in the antibody / antibody construct / antibody fragment (etc.) of “moiety (a)” in the inventive immunoconjugate(s) (as far as applicable), the heavy chain comprises at least one point mutation in Fc part that influences antibody-dependent cell-mediated cytotoxicity (ADCC), complementdependent cytotoxicity (CDC), serum half-life and / or glycosylation status of the antibody. It is to be understood to the skilled person that only antigen-binding fragments of said antibody that comprise the heavy chain, or the fragment thereof, may be encompassed herein. The at least one point mutation as referred to herein is preferably selected from L234A, L234F, L235A, L235E, L235Q, G236A, M252Y, S254T, T256E, S267E, H268F, N297A, K322A, K322Q, S324T, P331S, and I332E. More preferably, the at least one point mutation is selected from L234A, L235A, P331S and N297A. It is to be understood herein that the at least one point mutation may refer to more than one mutation. For example, in one preferred embodiment of the present invention, the heavy chain comprises L234A, L235A, P331S and N297A point mutations. As it is preferably to be understood herein, the amino acid positions as recited herein refer to the residue numbering as in lgG1 isotype. Should any other antibody class or isotype be used, the skilled person will be in position to translate the amino acid positions to any other antibody class or isotype known in the art.

[0377] The skilled person may also envisage including at least one mutation that increases antibody-dependent cell-mediated cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC). One possible combination is at least one mutation selected from S267E / H268F / S324T / G236A / I332E (EFTAE modification), preferably the mutations S267E / H268F / S324T / G236A / I332E (EFTAE modification).

[0378] The skilled person may further envisage including at least one mutation that counters the negative effect of N297A mutation (which allows for the production of deglycosylated antibodies). The antibody / antibody construct / antibody fragment (etc.) of “moiety (a)" in the inventive immunoconjugate(s) may be further modified to contain additional non-proteinaceous moieties that are known in the art and readily available. The moieties suitable for deri vatization of the antibody include but are not limited to water soluble polymers. Nonlimiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1 , 3-dioxolane, poly-1, 3,6- trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n vinyl pyrrolidone)polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide / ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.

[0379] Further modifications of the antibody are contemplated in the context of obtaining antibody conjugates with optimal in vitro and in vivo characteristics is via introduction of Cys residues at certain positions in the light or heavy chains of antibodies for site-specific bioconjugation that results in homogenous antibody labelling. THIOMAB™ thiol-engineering technology was developed by Genentech and has already been applied for the development of ADCs (DAR 2 or 4) via introduction of Cys at various positions, e.g., LC- S121C, LC-K149C, LC-V205C, HC-A114C, HC-A118C, HC-A121C, HC-S239C, HC-I239C, HC-S396C or HC-S442C. Further modifications of the antibody in order to prolong the serum half-life and increase internalization of therapeutic antibodies are also contemplated and encompassed by the present invention.

[0380] The antibody / antibody construct / antibody fragment (etc.) of “moiety (a)" in the inventive immunoconjugate(s) may also be further modified to contain additional moieties, thus yielding immunoconjugates comprising the antibody or the antigen-binding fragment thereof of the present invention. Said immunoconjugates are described herein. Antibodies may be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567. In one embodiment, isolated nucleic acid encoding an antibody described herein is provided. Such nucleic acid may encode an amino acid sequence comprising the VL and / or an amino acid sequence comprising the VH of the antibody (e.g., the light and / or heavy chains of the antibody).

[0381] An "isolated nucleic acid" refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extra chromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0382] Accordingly, for the production of the antibody / antibody construct / antibody fragment (etc.) of “moiety (a)” in the inventive immunoconjugate(s) ody, one or more vectors (e.g., expression vectors) comprising such nucleic acid are provided. It is to be understood that, unless indicated to the contrary, the terms polynucleotide and (isolated) nucleic acids may be used interchangeably.

[0383] The term "vector," as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors”. Thus, further provided is a vector comprising the polynucleotide encoding at least one variable heavy chain sequence and / or at least one variable light chain sequence as described herein.

[0384] As disclosed herein, further provided is a host cell comprising such nucleic acid. The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0385] As provided herein, a host cell comprises (e.g., has been transformed with): (1) a vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid that encodes an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid that encodes an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, e.g. a Chinese Hamster Ovary (CHO) cell or lymphoid ceil (e.g., YO, NSO, Sp2 / 0). In one embodiment, a method of making an antibody of the present invention is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody, as provided above, under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

[0386] For recombinant production of an antibody as described herein, nucleic acid encoding an antibody, e.g., as described above, is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell. Such nucleic acid may be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of the antibody).

[0387] Suitable host cells for cloning or expression of antibody-encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies may be produced in bacteria, in particular when glycosylation and Fc effector function are not needed. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vai. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing expression of antibody fragments in E. coli.) After expression, the antibody may be isolated from the bacterial cell paste in a soluble fraction and can be further purified.

[0388] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been "humanized," resulting in the production of an antibody with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[0389] Suitable host cells for the expression of glycosylated antibody are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculoviral strains have been identified which may be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells. Plant cell cultures can also be utilized as hosts. See, e.g., US Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0390] Vertebrate cells may also be used as hosts. For example, mammalian cell lines that are adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines are macaque kidney CV-1 line transformed by SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, e.g., in Graham et al., J. Gen Viral. 36:59 (1977)); baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); macaque kidney cells (CV I); African green macaque kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (WI38); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Ann. N. Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Vai. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0391] The antibody / antibody construct / antibody fragment (etc.) of ‘‘moiety (a)” in the inventive immunoconjugate(s) may, in one embodiment, include a further domain or a further amino acid sequence. For example, the antibody or the antigen-binding fragment thereof may include a localization sequence. Further examples of suitable include aldehyde tag and sortase recognition motif. The aldehyde tag is an artificial peptide tag recognized by the formylglycine-generating enzyme (FGE). A suitable example of an aldehyde tag is a tag according to sequence LCTPSR (SEQ ID NO.: 19), wherein upon FGE acting on said sequence, the cysteine residue is converted to formylglycine. The sortase recognition motif is according to sequence LPXTG (SEQ ID NO.: 20), wherein X can be any natural amino acid residue. The sortase enzyme, for example Staphylococcus aureus sortase, is a transpeptidase that attaches surface proteins to the cell wall; it cleaves between the Gly and Thr of the LPXTG motif and catalyzes the formation of an amide bond between the carboxyl-group of threonine and the amino-group of the cell-wall peptidoglycan. As known to the skilled person, sortase recognition motif allows for attachment of further peptidic moieties. As mentioned before, the immunoconjugate of the present invention comprises (as “moiety (b)”) a compound according to formula (I):

[0392] In formula (I), R1is selected from -H, C1-5 alkyl, -OH, -CN and -NO2. Preferably, R1is -H or -OH. More preferably, R1is -H.

[0393] In formula (I), R2is selected from -H, halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -CN, -NO2, -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl). Preferably, R2is selected from -H, halogen, -OH, -CN, -CONH2, - CONH(CI-5 alkyl), and -CON(C1-5 alkyl)(C1-5 alkyl). More preferably R2is -H, halogen or -CN. Even more preferably, R2is - halogen or -CN. Again more preferably, R2is -CN. Alternatively, R2is halogen, such as -Cl„

[0394] In formula (I), R3is selected from -H, halogen, C1-5 alkyl, aryl, -OH, -O(C1-5 alkyl), -CN, -NO2, -NH2, - NH(C1-5 alkyl), -N(C1-5 alkyl)(Ci.5alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), - CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl). Preferably, R3is selected from -H, halogen, and C1-5 alkyl. More preferably, R3is selected from -H and C1-5 alkyl (such as methyl). Even more preferably, R3is C1.5 alkyl (such as methyl). Again more preferably, R3is methyl.

[0395] In formula (I), R4is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(Ci-s alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(Ci.5alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -S02N(C1-5 alkyl)(C1-5 alkyl).

[0396] In formula (I), R5is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(Ci-s alkyl), -N(Ci-s alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(Ci.5alkyl)(Ci.5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(CI-5 alkyl)(C1-5 alkyl). Preferably, R4is selected from -H and halogen. More preferably, R4is -H.

[0397] In formula (I), A is a phenyl or five- or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs. Preferably, A is a phenyl or six-membered nitrogen-containing heteroaryl, optionally substituted with one or more groups selected from Rs. More preferably, A is a phenyl, optionally substituted with one or more groups selected from Rs.

[0398] In formula (I), each Rsis independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -O(C1-5 alkyl), -(C1-5 alkylene)-OH , -CN, -NH2, -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)- N(CI-5 alkyl)(C1-5 alkyl), -O-(C1-5 alkylene)-NH2, -O-(C2-5alkylene)-NH(C1-5 alkyl), -O-(C2-5 alkylene)-N(Ci. 5 alkyl)(C1-5 alkyl), -N02, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci.5alkyl), - CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(CWalkyl) and -SO2N(CI.5alkyl)(C1-5 alkyl). Preferably, each Rsis independently selected from halogen, C1-5 alkyl, -OH, -O(C1-5 alkyl), -CN, -N02, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, - CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(Ci-5alkyl). Preferably, each Rsis independently selected from halogen, C1.5 alkyl, -OH, -O(C1-5 alkyl), -CN, and -NO2. More preferably, each Rsis independently selected from halogen, C1-5 alkyl, and -CN. Even more preferably, each Rsis independently selected from C1-5 alkyl, and -CN. Again more preferably, each Rsis -CN. However, in one embodiment, each Rsis independently C1-5 alkyl (such as methyl). In one embodiment, each Rsis independently halogen (such as -Cl or -F, preferably -F).

[0399] Preferably, in formula (I), A is a phenyl or five- or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs, preferably one or more groups selected from halogen, C1-5 alkyl, -OH, -O(C1-5 alkyl), -CN, -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci.5alkyl), - CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(CI.5alkyl)(C1-5 alkyl).

[0400] More preferably, A is a phenyl or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs, preferably one or more groups selected from halogen, C1-5 alkyl, -OH, -0(C1-5 alkyl), - CN, -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(Ci- 5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -S02NH2)-SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(Ci-5alkyl). Said six-membered heteroaryl is preferably a six-membered nitrogen containing heteroaryl, such as pyridinyl. Thus, in one embodiment, A is six-membered nitrogen containing heteroaryl (preferably a pyridyl), optionally substituted with one or more groups selected from Rs, preferably one or more groups selected from halogen, C1-5 alkyl, -OH, -0(C1-5 alkyl), -CN, -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, - COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(CI. 5 alkyl) and -S02N(C1-5 alkyl)(C1-5 alkyl).

[0401] Even more preferably, A is phenyl optionally substituted with one or more groups selected from Rs, preferably one or more groups selected from -H, halogen, C1-5 alkyl, -OH, -O(C1-5 alkyl), -CN, -NO2, - NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), - CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl), preferably a phenyl substituted with methyl or a phenyl substituted with -CN.

[0402] In one embodiment, A is a five-membered heteroaryl, optionally substituted with one or more groups selected from Rs, preferably one or more groups selected from halogen, C1-5 alkyl, -OH, -O(C1-5 alkyl), - CN, -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(Ci- 5 alkyl), -CON(CI-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(CI-5 alkyl) and -SO2N(CI-5 alkyl)(C1-5 alkyl).

[0403] Particularly preferred A is selected from 3-cyanophenyl, 3-cyanopyrid-5-yl, 2-cyano-3-fluorophenyl, 3- cyano-4-hydroxyphenyl, 4-aminomethylphenyl, 4-N-rnethyl-aminomethylphenyl, and 5-bromothien-2-yl.

[0404] Particularly preferred are embodiments of the compound of formula (I), wherein A is as defined hereinabove, including any preferred definition of A and any individual and specific disclosed embodiment of A, including each and every particularly preferred A as recited above, and wherein:

[0405] R1is -H, R2 is -CN, R3is -H, R4, is H, and R5is H;

[0406] R1is -H, R2is -CN, R3is -methyl, R4, is H, and R5is H;

[0407] Ri is -H, R2is -Cl, R3is -H, R4, is H, and R5is H;

[0408] R1is -H, R2is -Cl, R3is -methyl, R4, is H, and R5is H;

[0409] R1is -H, R2is -Cl, R3is -Cl, R4, is H, and R5is H;

[0410] It is particularly preferred that the compound of formula (I) is selected from:

[0411]

[0412] More preferably, the compound of formula (I) is selected from

[0413]

[0414] Further suitable compound of formula (

[0415] Further suitable compound of formula (I) is selected from the following compounds:

[0416] The compound of formula (I), as referred to herein and as comprised as “moiety (b)” in the immunoconjugate of the present invention, is, inter alia, capable of inducing degradation of RBM39, when contacted with RBM39 in the cell. Degradation here may refer to Ubiquitin induced degradation through proteasomal machinery, e.g. 26S proteasome, or degradation through any other mechanism that is apparent to the skilled person. The degradation of RBM39 manifests itself through reduced level of RBM39 in the cell, preferably to an extent that less than 10% of control level of RBM39 is present, more preferably to an extent that less than 1% of control level of RBM39 is present, even more preferably to an extent that no RBM39 can be detected anymore. Accordingly, when reference is made to the biological or technical effect of RBM39, it means a reference to its ability to induce the degradation of RBM39. Further accordingly, when reference is made to interaction between the compound of formula (I) and RBM39, a reference is made to an effect of causing said degradation of RBM39. As it is apparent to the skilled person, and as it follows from the following, the interaction between the compound of formula (I) and RBM39 is preferably a ternary interaction involving the compound of formula (I), RBM39 and DCAF15, an E3 ubiquitin ligase.

[0417] Three recent publications have provided detailed structural evaluation of the binding mechanism of aryl sulfonamide drugs E782024'25and indisulam,26respectively and results and observations made in these studies are summarized below. According to one of these works (see Fig. 1), the two sulfonyl oxygens of E7820 form hydrogen bonds with the backbone amide nitrogens on Ala234 and Phe235 AA side chains of DCAF15, while the indole nitrogen and sulfonamide nitrogen form extensive water-mediated hydrogen bonds with the side chain oxygens on Thr262 and Asp264 of RBM39. Additional hydrogen bonds between the indole nitrogen and backbone carbonyl oxygen of DCAF15 Phe231 together with the hydrophobic interactions of the C4 methyl of E7820 with Val477 and Val556 AA residues of DCAF15 are crucial for the high affinity to DCAF15. Swapping the methyl for a hydrogen, as in indisulam ordesmethyl-E7820, results in a substantial loss of DCAF15 binding. The phenyl ring forms a T-shaped IT— IT interaction with Phe235 of DCAF15 and is situated in a spacious pocket allowing for structural diversity as observed in indisulam.

[0418] As for indisulam (see Fig. 2), the chloro-indole group of indisulam binds in a hydrophobic pocket comprising of Thr230, Phe235 and Val559 of DCAF15, as well as Met265 of RBM39. The phenylsulfonamide is positioned between several aliphatic side chains, including Ala234, Thr262 of DCAF15 and Met265 side chain of RBM39. The central sulfonamide accepts two hydrogen bonds from the main chain amides of DCAF15 Ala234 and Phe235 and its nitrogen forms water-mediated hydrogen bonds with both Thr262 and Asp264 of RBM39.

[0419] A compound capable of inducing degradation of RBM39 is accordingly a compound, which contacted with RBM39 in the cell, induces degradation of RBM39, as described herein. Particularly preferred compounds that are RBM39 degraders are the compounds of formula (I), as referred to herein and as defined herein. However, skilled person will recognize that other degraders of RBM39 exist and may also be used In the immunoconjugate. For example, suitable RBM39 degrades are further disclosed in US 11 ,807,606 B2. Further suitable examples of RBM39 degraders are disclosed in WO 2024 / 039689. Further suitable RBM39 degraders are disclosed in WO 2022 / 169755 and WO 2024 / 129634. Further RBM39 degraders are disclosed in WO 2024229040.

[0420] A compound capable of inducing degradation of RBM39, as defined herein, may also be referred to as RBM39 MGD, which stands for molecular glue degrader.

[0421] It is to be understood that the compound of formula (I), as defined herein, including any individually disclosed compound of formula (I), are attached to “moiety (a)”, preferably to the antibody, the antibody fragment and / or the antibody constructs as comprised in the inventive immunoconjugates. This attachment should lead to a covalent binding of “moiety (a)” to “moiety (b)” in the inventive immunoconjugates. To this end, the skilled person will understand that formally the compound of formula (I) is to be transformed into a monovalent radical, or, in other words, into a monovalent group (or monovalent moiety), by detachment of an H atom from the compound. Particular selection of the attachment point depends on available chemistry for attachment to (a). Furthermore, particular selection of attachment point and applied chemistry must be tolerated from the point of view of interaction with RBM39.

[0422] In order to facilitate the chemical linker attachment and antibody bioconjugation, E7820, the most potent hit from the degrader payload screen was modified with an aminomethyl functionality according to the published procedure26to obtain compound AMe-deCN-E7820 / JKW-48 and its cytotoxic activity was tested in neuroblastoma cell lines using cell viability assay. Such modification leads to decrease in the anti-cancer activity of JKW-48 compared to the parent molecule E7820 (Table 2).

[0423] Accordingly, to further improve the potency of the RBM39 degrader payload, based on the above observations and literature review, molecules with chemical structures consisting of the 7-amino-indole core of either E7820 or indisulam combined with substituted or modified benzenesulfonamide moieties based on either E7820 or indisulam and methylated derivatives were proposed, designed and synthesized. Table 2. In vitro biological activity (EC50 [nM]) of synthesized RBM39 SM degraders in selected neuroblastoma cell lines compared to investigational RBM39 degrader drugs E7820 or indisulam.

[0424] The aim of this SAR study was to assess the effect of the indole moiety and aryl ring substitution on the biological / anti-cancer activity of this class of RBM39 molecular glue degraders. E7820 indole moiety was combined with the indisulam aryl moiety and vice versa (similar analogy was used for the bromo-thienyl portion of tasisulam, another reported RBM39 degrader). It appears that indole moieties bearing methyl and cyano group substituents are more favored. Furthermore, the effects of the methyl and chloride substitution on the indole ring were also investigated. Methylation of the terminal sulfonamide on indisulam should lead to increased hydrophobicity of the molecule which might be beneficial for the degradation activity . Finally, cyano substituent on the phenyl ring seems to be important for the potency of the degrader and therefore it was retained whilst additional substituents which could potentially change the aromaticity of the phenyl ring (e.g., enhancing the T-shaped pi-pi interaction with F235 on DCAF15) or would allow for the formation of additional hydrogen bonds with the nearby amino acid residues were introduced.

[0425] Accordingly, and as demonstrated by the present inventors, the compound of formula (I) can be attached to "moiety (a)” of the inventive immunoconjugates, preferably to the antibody / antibody fragment / antibody construct of “moiety (a)”, through N atom in the sulfonamide moiety of the compound of formula (I). Thus, the present invention relates to an embodiment, wherein the compound of formula (I) is present in the immunoconjugate as a moiety of formula (la):

[0426] wherein R1, R2, R3, R4, R5and A are as defined for formula (I).

[0427] In formula (la), it is preferred that R1, and / or R4, and / or R5are each independently -H. More preferably, R1, R4, and R5are each -H.

[0428] In formula (la), It is further preferred that R2, is halogen (such as -Cl) or -CN. More preferably, R2is -CN. Alternatively, R2is halogen (such as -Cl), more preferably, R2is -Cl.

[0429] In formula (la), preferably R3is C1.5 alkyl (such as methyl). More preferably, R3is methyl.

[0430] Thus, in one particularly preferred embodiment, the moiety of formula (la) is a moiety of formula (la-1):

[0431] Alternatively, and as demonstrated by the present inventors, the compound of formula (I) can be attached to (a), preferably to the antibody of (a), through A ring, for example through amino group of the A moiety being (optionally substituted) 4-aminomethylphenyl. Thus, accordingly, the present invention relates to the immunoconjugate of the present invention, wherein the compound of formula (I) is present in the immunoconjugate as a moiety of formula (lb):

[0432] In formula (lb) R1, R2, R3, R4, and R5are as defined for formula (I), Rsis as defined for formula (I), preferably Rsselected from halogen, C1.5 alkyl, C1-5 haloalkyl, -OH, -O(C1-5 alkyl), -CN, -NO2, -NH(Ci-s alkyl), -N(C1-5 alkyl)(Ci.5alkyl), -CHO, -COOH, -COO(Ci.5alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(CI.5alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(CI-5 alkyl) and -SO2N(CI-5 alkyl)(C1-5 alkyl), and n is an integer from O to 4.

[0433] Accordingly, and preferably, in formula (lb), R1, and / or R4, and / or R5are each independently -H. More preferably, R1, R4, and R5are each -H.

[0434] In formula (lb), It is further preferred that R2, is halogen (such as -Cl) or -CN. More preferably, R2is -CN. Alternatively, R2is halogen (such as -Cl), more preferably, R2is -Cl.

[0435] In formula (lb), preferably R3is C1.5 alkyl (such as methyl). More preferably, R3is methyl.

[0436] In formula (lb), preferably n is 0 or 1 . More preferably, n is 0. Accordingly, the phenyl ring in A in formula (lb) is not further substituted. In a particularly preferred embodiment, the moiety of formula (lb) is a moiety of formula (lb-1), as outlined in the following:

[0437] In formula (lb-1), R1, R2, R3, R4, and R5are as for formula (lb), and wherein n is an integer from 0 to 4.

[0438] Accordingly, and preferably, in formula (lb), that R1, and / or R4, and / or R5are each independently -H. More preferably, R1, R4, and R5are each -H.

[0439] In formula (lb), It is further preferred that R2, is halogen (such as -Cl) or -CN. More preferably, R2is -CN.

[0440] Alternatively, R2is halogen (such as -Cl), more preferably, R2is -Cl. In formula (lb), preferably R3is C1-5 alkyl (such as methyl). More preferably, R3is methyl.

[0441] Thus, in a particularly preferred embodiment, the moiety of formula (lb-1) is a moiety of formula (lb-2), as outlined in the following:

[0442] The attachment of the compound of formula (I) (or, more broadly speaking, of a RBM39 degrader) to (a), such as to an antibody of (a), is not to be particularly limited in any way, and accordingly, any feasible attachments that are apparent to the skilled person, are encompassed. Particularly preferred are attachments as shown in formulae (la) and following, as well as (lb) and the following. it is to be understood that the compound of formula (I) (i.e. “moiety (b)” of the immunoconjugate(s) of the present invention) may be attached to “moiety (a)”, such as an antibody / antibody fragment / antibody construct / binding moiety, preferably an antibody / antibody moiety, directly, or it may be attached through a particular linker. Preferably, the compound of formula (I) is attached to (a) through a linker.

[0443] The linker moiety (or the linker), as referred to herein, is not meant to be particularly limited and any linker that is conceivable to the skilled person is considered encompassed by the present invention.

[0444] In the immunoconjugate of the present invention, particularly preferred is a linker comprising a moiety according to formula (II):

[0445] -L1-L.P-L2-X- which is defined in the following. Accordingly, and in other words, in one embodiment of the present invention, the immunoconjugate comprises a moiety according to formula (II): -Li-Lp-L2-X-

[0446] (H)-

[0447] In formula (II), Li is C2-20 alkylene, optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may independently be replaced by a group selected from -CH=CH-, -CEC-, -O-, -NR’-, -CO-, CMO arylene, 5-6 membered heteroarylene, - (CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR’-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0448] To the skilled person, it is immediately apparent that Li is a bivalent moiety, or in other words a moiety with two attachment points. Accordingly, it is to be understood that Li is attached to (a), in particular to the antibody of (a), and Li is attached to Lp.

[0449] Preferably, Li is C2-12 alkylene, optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may independently be replaced by a group selected from -O-, -NR’-, -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, C3-C11 cycloalkylene, and 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl.

[0450] More preferably, Li is C2-12 alkylene, wherein one or more -CH2- groups may independently be replaced by a group selected from -CO-, -(CH2-O-CH2)-, -(CH2-CH2-O)-, and C3-C11 cycloalkylene.

[0451] Accordingly, different Li are conceivable to the skilled person. For example, Li is selected from:

[0452] It is to be understood that, as Li is a bivalent moiety, and includes two attachment points, its directionality is to be defined. Accordingly, it is preferred that the right empty valence of Li as shown herein, is attached to Lp. It follows that the left empty valence of Li is preferably attached to (a), in particular to the antibody of (a). O O

[0453] In one embodiment, Li is . It is preferred that the right empty valence of Li as shown herein, is attached to LP. It follows that the left empty valence of Li is preferably attached to (a), in particular to the antibody of (a).

[0454] In one embodiment, Li is It is preferred that the right empty valence of Li as shown herein, is attached to Lp. It follows that the left empty valence of Li is preferably attached to (a), in particular to the antibody of (a).

[0455] In one embodiment, preferred that the right empty valence of Li as shown herein, is attached to LP. It follows that the left empty valence of Li is preferably attached to (a), in particular to the antibody of (a).

[0456] It is however particularly preferred that in the immunoconjugate of the present invention, as defined herein, 0 comprising the moiety of formula (II), the Li is , wherein the right empty valence of

[0457] Li is atached to LP.

[0458] More preferably, in said immunoconjugate, the Li is , wherein the right empty valence of Li is attached to LP.

[0459] Even more preferably, in said immunoconjugate, the Li is wherein the right empty valence of Li is attached to Lp.

[0460] As apparent to the skilled person, Li may also be a trivalent moiety, such as the following moiety: wherein the left side is attached to antibody, and two empty valences on the right side are atached to a different occurrence of Lp.

[0461] In formula (II), LP is a bond or is a peptide linker which includes up to 5 amino acid residues, wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2 or to X. It is accordingly to be understood that the N-terminus of the peptide linker is connected to Li. It is further preferred that Li comprises a -CO- moiety, through which it is atached to Lp. Accordingly, it is preferred that Li and Lp are connected with each other through an amide bond (-CO-NH-).

[0462] Lp is preferably a peptide linker which includes up to 5 amino acid residues. Accordingly, Lp may include 1 , 2, 3, 4, or 5 amino acid residues. Preferably, Lp includes between 2 and 4 amino acid residues. Accordingly, Lp may include 2, 3 or 4 amino acid residues.

[0463] Suitable peptide linkers as Lp include -Val-Cit-, -cBu-Cit-, -Val-Ala-, -Glu-Val-Cit-, -Gly-Gly-Gly-, -Ala-Ala- Asn- and -Gly-Gly-Phe-Gly- (SEQ ID NO.: 28), wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2 or to X, and wherein the N-terminus is connected to Li.

[0464] As understood herein, -Val-Cit- is a peptide linker according to formula:

[0465] As understood herein, -cBu-Cit- includes a modified amino acid residue comprising a 1 ,1 -cyclobutylene moiety. This peptide linker is according to formula:

[0466] As understood herein, -Glu-Val-Cit- is a peptide linker according to formula:

[0467] Thus, preferably LP is selected from -Val-Cit-, -cBu-Cit-, -Vai-Ala-, -Glu-Val-Cit-, -Gly-Gly-Gly-, -Ala-Ala- Asn- and -Gly-Gly-Phe-Gly- (SEQ ID NO.: 28), wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2 or to X, and wherein the N-terminus is connected to Li.

[0468] Particularly preferred LP is -Gly-Gly-Phe-Gly- (SEQ ID NO.: 28), wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2or to X, and wherein the N-terminus is connected to Li.

[0469] However, in one embodiment, the peptide linker Lp is -Val-Cit-, wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2or to X, and wherein the N-terminus is connected to Li.

[0470] Alternatively, in one embodiment, LP is -Ala-Ala-Asn-, wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2or to X, and wherein the N-terminus is connected to Li.

[0471] In formula (II), L2is -NH-1 ,4-phenylene-CH2- or a bond. Preferably, L2is -NH-1 ,4-phenylene-CH2-. In other words, L2is preferably a moiety according to formula:

[0472] It is to be understood that L2 is to be attached to LP (or, if LP is a bond, to Li), through its -NH- group. Thus, it is to be understood that L2 is preferably to be attached to LP (or, if LP is a bond, to Li), through an amide bond.

[0473] In formula (II), X is selected from a bond, -O-, -O-CO-, -CO-O-, -O-CO-NH-, -O-CO-NH-CH2- and -NH-, wherein X is atached to the compound of formula (I). Preferably, X is selected from a bond, -O-, -O-CO-, -CO-O-, and -NH-, wherein X is attached to the compound of formula (I).

[0474] Preferably, X is -O-CO-, wherein the right empty valence of said -O-CO- is attached to the compound of formula (I). In this embodiment, is it particularly preferred that (b) the compound of formula (I) is present as a moiety according to formula (lb). Thus, it this specific embodiment, wherein X is -O-CO-, the right empty valence of said -O-CO- is connected to the moiety of formula (lb).

[0475] Alternatively, X is a bond. It is particularly preferred that (b), the compound of formula (I), is present as a moiety according to formula (la). Thus, in this specific embodiment, wherein X is a bond, the (b) is according to formula (la).

[0476] X may also be -O-CO-NH-CH2-, wherein the right empty valence of said -O-CO-NH-CH2- is attached to the compound of formula (I). In this embodiment, is it particularly preferred that (b) the compound of formula (I) is present as a moiety according to formula (la), more preferably as a moiety according to formula (la-1). Thus, it this specific embodiment, wherein X is -O-CO-NH-CH2-, the right empty valence of said -O-CO-NH-CH2- is connected to the moiety of formula (la) (preferably moiety of formula (la-1). In other words, it is preferred that methylene group in -O-CO-NH-CH2- is connected to nitrogen atom with empty valence in formula (la) (such as formula (la-1).

[0477] X may also be -O-CO-NH-, wherein the right empty valence of said -O-CO-NH- is attached to the compound of formula (I).

[0478] Different strategies for attachment to (a) or, more specifically, the antibody of (a), are contemplated. Particularly preferred in the context of the present invention is site-specific antibody conjugation via Cys- thiol reaction. In this context particularly preferred is maleimide-thiol conjugation, which allows for the attachment of payload-containing compounds to Cys residues in (a), and in particular in the antibody of (a). In the course of such reaction, the conjugate is formed comprising a moiety according to formula (Ila):

[0479] -Z-LI-L.P-L.2-X-

[0480] (Ha).

[0481] In formula attached through its right empty valence to Li, and through its left empty valence to a cysteine residue of the antibody,

[0482] Furthermore, in formula (Ila), Li, Lp, L2, and X are as defined in formula (II), including any specific embodiment of this formula or any preferred definition of formula (II).

[0483] Accordingly, in other words, preferably in the immunoconjugate of the present invention, the moiety of formula (II) is comprised in a moiety of formula (Ila):

[0484] -Z-L1-LP-L2-X-

[0485] (lia), as defined herein.

[0486] The immunoconjugate may also be defined according to the process of its production, and in particular through substrates of the conjugation reaction and the reaction itself. Accordingly, in one preferred embodiment, the immunoconjugate of the present invention is obtainable in the reaction of the compound comprising a moiety of formula

[0487] ZI-LI-LP-L2-X-

[0488] (llb) with -SH group of cysteine of the antibody.

[0489] In formula (lib), Z1 is a group that can react (i.e., is capable of reacting) with -SH of cysteine to form a covalent bond with said cysteine, Such group may be an unsaturated group, in particular unsaturated group including at least one double or triple bond. Such group may be a Michael acceptor, which is known to the skilled person to react with -SH group of cysteine.

[0490]

[0491] Alternatively, Z1 may be a phosphonamidite-based group, i.e., a group selected from More preferably, in formula (lib),

[0492] In formula (lib), Li , Lp, L2, and X are as defined for the formula (II), including any specific embodiment of formula (II) and any preferred definition of formula (II).

[0493] Alternatively, in order to achieve homogenous labeling and obtain immunoconjugates with an average DAR 4, the compound of formula (I) (or, referring to more generally, RBM39 degrader) can be attached to the antibody using a bioconjugation protocol consisting of a controlled TCEP (tris(2- carboxyethyl)phosphine)-mediated antibody disulfide bond reduction followed by a site-specific bioconjugation via rebridging of disulfide of a compound comprising a moiety of formula (lie):

[0494] Z2-L1-LP-L2-X- (llc).

[0495] In formula (lie), Z2is a group that can react with two -SH of cysteine to form a covalent bond with each cysteine. Preferably, Z2is selected from , wherein each

[0496] Rzindependently is Hal (such as Cl, Br or I) or -S-aryl (such as -S-pheny I

[0497] , wherein Rxis C1.5 alkyl (such as methyl or ethyl), C2-5 alkenyl or C2-5 alkynyl (such as propargyl).

[0498] In formula (lie), Li, LP, L2Jand X are as defined in formula (II), including any specific embodiment of formula (II) and any preferred definition of formula (II).

[0499] As however mentioned before, the strategy for linking the RBM39 degrader is not meant to be particularly limited and any particular strategy recognizable to the skilled person can be used in the immunoconjugates of the present invention.

[0500] For example, for the compounds being hydrophobic payloads, a conjugation relying on self-immolative linker bearing a moiety derived from glucuronic acid can be employed. Accordingly, such conjugate is released in the cell according to P-glucuronidase-based mechanism, followed by 1 ,6-elimination, which is summarized in the following scheme:

[0501]

[0502] Accordingly, in one embodiment, the immunoconjugate of the invention includes the moiety of formula wherein the RBM39 degrader is attached to an empty valence of carbonyl group, and wherein the antibody is attached (directly or indirectly, for example via -Z-Li-, as described herein) to an empty valence of -NH- group.

[0503] In one embodiment, the immunoconjugate of the invention includes the moiety of formula wherein the RBM39 degrader is attached to an empty valence of methylene group (preferably through nitrogen atom of a sulfonamide group), and wherein the antibody is attached (directly or indirectly, for example via -Z-L1-, as described herein) to an empty valence of -NH- group.

[0504] Herein, the drug refers to a compound of formula (I), or more generally, an RBM39 degrader. Alternatively, a linker comprising a moiety derived from galactose may be used, which is released in the cell in a 0- galactosidase-catalyzed reaction, as shown in the following:

[0505] Accordingly, in one embodiment, the immunoconjugate of the invention includes the moiety of formula wherein the RBM39 degrader is attached to an empty valence of carbonyl group, and wherein the antibody is attached (directly or indirectly, for example via -Z-L1-, as described herein) to an empty valence of -NH- group.

[0506] In one embodiment, the immunoconjugate of the invention includes the moiety of formula wherein the RBM39 degrader is attached to an empty valence of CH group (preferably through nitrogen atom of a sulfonamide group), and wherein the antibody is attached (directly or indirectly, for example via -Z-Li-, as described herein) to an empty valence of -NH- group. Encompassed by the present invention are further bioconjugation strategies, for example a strategy based on enzymatic glycan remodeling followed by metal-free click-chemistry attachment, as described in Wijdeven et al., 2002, mAbs, 14(1), e2078466, https: / / doi.org / 10.1080 / 19420862.2022.2078466. Further labeling strategies may be based on introducing particular sequences in the protein that can undergo further modification. The examples of such suitable sequences include aldehyde tag and sortase recognition motif.

[0507] The aldehyde tag is an artificial peptide tag recognized by the formylglycine-generating enzyme (FGE). A suitable example of an aldehyde tag is a tag according to sequence LCTPSR (SEQ ID NO.: 19), wherein upon FGE acting on said sequence, the cysteine residue is converted to formylglycine, which can be used in further attachment strategies.

[0508] The sortase recognition motif is according to sequence LPXTG (SEQ ID NO.: 20), wherein X can be any natural amino acid residue. The sortase enzyme, for example Staphylococcus aureus sortase, is a transpeptidase that attaches surface proteins to the cell wall; it cleaves between the Gly and Thr of the LPXTG motif and catalyzes the formation of an amide bond between the carboxyl-group of threonine and the amino-group of the cell-wall peptidoglycan. As known to the skilled person, sortase recognition motif allows for attachment of further peptidic moieties, and can also be used for conjugating the compound of formula (I) to the antibody, to yield an immunoconjugate, as provided herein.

[0509] It is further apparent to the skilled person that labeling strategy based on transglutaminase can be used for attaching the metal chelator to the antibody. Transglutaminases catalyze an acyl-transfer reaction to the side chain of glutamine residues of their protein substrate. Depending on the acyl donor, this can result in an amide bond between the glutamine and a primary amine, crosslinking between two proteins via a side chain lysine of the donor protein or the deamidation of glutamine. For protein labelling purposes, the acyl-transfer reaction is preferred. While transglutaminases are specific for glutamine on the target protein, the flexibility in terms of the amine containing acyl-donor offers diverse possibilities for modification. In contrast to other protein-ligation strategies, the probe containing reactant is not required to be a peptide and can simply be an alkylamine or an oligoamine as long as it contains a primary amine. For example, the compound of formula (I) can be attached to a peptide comprising a peptide sequence suitable for attachment to the antibody via transglutaminase-catalyzed reaction. One example of such sequence Is RAKAR sequence (SEQ ID NO.: 21). Further such sequences are disclosed in WO 2019 / 057772.

[0510] The antibody may also optionally include one or more non-canonical amino acids to be used for coupling of said antibody with another chemical entity. Said amino acids may include residues that would be reactive in addition reactions known to the skilled person as bioorthogonal chemistry approaches. Of these of particular importance is click chemistry, well known to the skilled person. Suitable examples of such residues include residues comprising azide moiety, or cyclooctyne moiety or a moiety being capable to perform an inverse-demand Diels-Alder cycloaddition reaction e.g., a trans-cyclooctene / tetrazine reaction pair. However, the invention is not meant to be limited to any of these examples, and other such residues known to the skilled person may also be used. The methods of producing antibodies (or fragments thereof, as applicable) comprising non-canonical amino acid residue(s) using recombinant methods are known to the skilled person. A further suitable example of biorthogonal chemistry approach is sulfur (VI) fluoride exchange chemistry.

[0511] The present invention is further not limited in any way with respect to the compound of formula (l)-antibody ratio (also referred to as drug-to-antibody ratio, i.e., DAR), and any obtainable ratio can be used in the immunoconjugate of the present invention. For example, the drug / antibody ratio may be between 1 and 8, preferably between 3 and 5, such as 3.0, 3.1 , 3.2, .3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9 or 5.0. Preferably, said ratio is between 3.5 and 4.5. Particularly preferred is ratio of about 4.0, such as 4.0. Alternatively, it is preferred that the drug / antibody ratio is between 5 and 7, such as 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1 , 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. Particularly preferred ratio is about 6.0, such as 6.0. However, the drug antibody ratio can also be between 7 and 8, such as 7.0, 7.1 , 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. Particularly preferred ratio is about 8.0, such as 8.0.

[0512] A preferred immunoconjugate of the present invention comprises:

[0513] (a) dinutuximab beta antibody (ch14.18 / CHO, Qarziba®) or dinutuximab antibody (ch14.18, Unituxin®), i.e., antibody comprising a heavy chain comprising an amino acid sequence according to SEQ ID NO.: 15 and comprising a light chain comprising an amino acid sequence according to SEQ ID NO.: 16, and

[0514] (b) a moiety of formula (I b-2), as outlined in the following

[0515] (lb-2)

[0516] Further, a preferred immunoconjugate of the present invention also comprises: (a) dinutuximab beta antibody (ch14.18 / CHO, Qarziba®) or dinutuximab antibody (ch14.18, Unituxin®), i.e. , antibody comprising a heavy chain comprising an amino acid sequence according to SEQ ID NO.: 15 and comprising a light chain comprising an amino acid sequence according to SEQ ID NO.: 16, and

[0517] (b) a moiety of formula (la-1 ), as outlined in the following

[0518] (la-1 )

[0519] Preferably, the antibody / antibody construct (etc.) of “moiety (a)” of the inventive immunoconjugate further comprises a moiety according to formula (Ila):

[0520] -Z-L1-L.p-L.2-X-

[0521] (lla). wherein attached through its right empty valence to Li , and through its left empty valence to a cysteine residue of the antibody;

[0522] Li wherein the right empty valence of Li is attached to Lp, and the left empty valence is attached to Z;

[0523] Lp is -Gly-Gly-Phe-Gly- (SEQ ID NO.: 28), wherein the C-terminus of the peptide linker is connected to - NH- moiety of L2, and wherein the N-terminus is connected to Li ;

[0524] L2 is a moiety according to formula wherein L2 is atached to LP through its -NH- group;

[0525] X is -O-CO-, and the right empty valence of said -O-CO- is connected to (b). It is to be understood that the right empty valence of said -O-CO- is connected to the empty valence in (lb-2) formula.

[0526] Particularly preferred immunoconjugate of the invention may also be defined as being obtainable in a reaction of a compound according to formula: and dinutuximab beta antibody (ch14.18 / CHO, Qarziba®), or dinutuximab antibody, as defined herein, i.e., an antibody comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence GSSFTGYN (SEQ ID NO.: 29), a CDR-H2 having the amino acid sequence IDPYYGGT (SEQ ID NO.: 30), and a CDR-H3 having the amino acid sequence VSGMEY (SEQ ID NO.: 31), and a light chain variable region comprising a CDR-L1 having the amino acid sequence QSLVHRNGNTY (SEQ ID NO.: 32), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence QSTHVPPLT (SEQ ID NO.: 33). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0527] EVQLLQSGPELEKPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRA

[0528] TLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS (SEQ ID NO.: 34), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence.

[0529] EIVMTQSPATLSVSPGERATLSCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFS GSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK (SEQ ID NO.: 35). More preferably, said antibody comprises a heavy chain comprising an amino acid sequence according to SEQ ID NO.: 15 and a light chain comprising an amino acid sequence according to SEQ ID NO.: 16.

[0530] Further particularly preferred immunoconjugate of the invention may also be defined as being obtainable in a reaction of a compound according to formula: and dinutuximab beta antibody (ch14.18 / CHO, Qarziba®), or dinutuximab antibody, as defined herein, i.e., an antibody comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence GSSFTGYN (SEQ ID NO.: 29), a CDR-H2 having the amino acid sequence IDPYYGGT (SEQ ID NO.: 30), and a CDR-H3 having the amino acid sequence VSGMEY (SEQ ID NO.: 31), and a light chain variable region comprising a CDR-L1 having the amino acid sequence QSLVHRNGNTY (SEQ ID NO.: 32), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence QSTHVPPLT (SEQ ID NO.: 33). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0531] EVQLLQSGPELEKPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRA TLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS (SEQ ID NO.: 34), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0532] EIVMTQSPATLSVSPGERATLSCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIHKVSNRFSGVPDRFS GSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK (SEQ ID NO.: 35). More preferably, said antibody comprises a heavy chain comprising an amino acid sequence according to SEQ ID NO.: 15 and a light chain comprising an amino acid sequence according to SEQ ID NO.: 16.

[0533] Further particularly preferred immunoconjugate of the invention may also be defined as being obtainable in a reaction of a compound according to formula: and dinutuximab beta antibody (ch14.18 / CHO, Qarziba®), or dinutuximab antibody, as defined herein, i.e. , an antibody comprising a heavy chain variable region comprising a CDR-H1 having the amino acid sequence GSSFTGYN (SEQ ID NO.: 29), a CDR-H2 having the amino acid sequence IDPYYGGT (SEQ ID NO.: 30), and a CDR-H3 having the amino acid sequence VSGMEY (SEQ ID NO.: 31), and a light chain variable region comprising a CDR-L1 having the amino acid sequence QSLVHRNGNTY (SEQ ID NO.: 32), a CDR-L2 having the amino acid sequence KVS, and a CDR-L3 having the amino acid sequence QSTHVPPLT (SEQ ID NO.: 33). Preferably, said antibody comprises a heavy chain variable domain (VH) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0534] EVQLLQSGPELEKPGASVMISCKASGSSFTGYNMNWVRQNIGKSLEWIGAIDPYYGGTSYNQKFKGRA TLTVDKSSSTAYMHLKSLTSEDSAVYYCVSGMEYWGQGTSVTVSS (SEQ ID NO.: 34), and a light chain variable domain (VL) having an amino acid sequence with at least 80% sequence identity to, preferably with at least 90% sequence identity to, more preferably with at least 95% sequence identity to, even more preferably with at least 97% sequence identity to, again more preferably with at least 99% sequence identity to, still more preferably identical to, the amino acid sequence:

[0535] EIVMTQSPATLSVSPGERATLSCRSSQSLVHRNGNTYLHWYLQKPGQSPKLUHKVSNRFSGVPDRFS GSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPPLTFGAGTKLELK (SEQ ID NO.: 35).

[0536] More preferably, said antibody comprises a heavy chain comprising an amino acid sequence according to SEQ ID NO.: 15 and a light chain comprising an amino acid sequence according to SEQ ID NO.: 16.

[0537] In one embodiment, the present invention relates to a compound of formula (III):

[0538] ZZ-LI-LP-L2-X-Y

[0539] (III) or a pharmaceutically acceptable salt thereof.

[0540] In formula (III), Z is Zi or Z2. Preferably, Z is Z1.

[0541]

[0542] Alternatively, Z1 may be a phosphonamidite-based group, i.e., a group selected from

[0543] More preferably, In formula (III), Z2 is selected from wherein each Rzindependently is Hal (such as Cl, Br or I) or -S-aryl (such as -S-phenyl), wherein Rxis C1-5 alkyl (such as methyl or ethyl), C2-5 alkenyl or C2-5 alkynyl (such as propargyl).

[0544] In formula (III), Li , LP, L2, and X are as defined for formula (II), including any specific embodiment of formula (II) and including any preferred definition of formula (II).

[0545] In formula (III), Y is the moiety of formula (la), including any specific embodiments and preferred definitions of this formula, or the moiety of formula (lb), including any specific embodiments and preferred definitions of the formula.

[0546] The compound of formula (III) is useful for attaching the compound of formula (I) to the antibody.

[0547] A particularly preferred compound of formula (III) is a compound according to formula:

[0548] A further particularly preferred compound of formula (III) is a compound according to formula:

[0549] A further particularly preferred compound of formula (III) is a compound according to formula:

[0550] The scope of the invention embraces all pharmaceutically acceptable salt forms of the compounds of formula (III) which may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of an acid group (such as a carboxylic acid group) with a physiologically acceptable cation. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N,N- dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts (such as, e.g., sulfate or hydrogensulfate salts), nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts, perchlorate salts, borate salts, or thiocyanate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate (embonate), camphorate, glucoheptanoate, or pivalate salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; glycerophosphate salts; and acidic amino acid salts such as aspartate or glutamate salts. Preferred pharmaceutically acceptable salts of the compounds of formula (III) include a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, and a phosphate salt. A particularly preferred pharmaceutically acceptable salt of the compound of formula (III) is a hydrochloride salt. Accordingly, it is preferred that the compound of formula (III), Including any one of the specific compounds of formula described herein, is in the form of a hydrochloride salt, a hydrobromide salt, a mesylate salt, a sulfate salt, a tartrate salt, a fumarate salt, an acetate salt, a citrate salt, or a phosphate salt, and it is particularly preferred that the compound of formula (III) is in the form of a hydrochloride salt.

[0551] The present invention also specifically relates to the compound of formula (III), including any one of the specific compounds of formula (III) described herein, in non-salt form.

[0552] The following definitions apply throughout the present description and claims, unless explicitly indicated to the contrary.

[0553] The term “hydrogen” is herein used to refer to protium, deuterium and / or tritium, preferably to protium. Accordingly, the term “non-hydrogen atom” refers to any atoms that is not hydrogen, i.e. that is not protium, deuterium or tritium.

[0554] The term “hydrocarbon group” refers to a group consisting of carbon atoms and hydrogen atoms.

[0555] The term “alicyclic” is used in connection with cyclic groups and denotes that the corresponding cyclic group is non-aromatic. As used herein, the term “alkyl” refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group which may be linear or branched. Accordingly, an “alkyl” group does not comprise any carbon-to- carbon double bond or any carbon-to-carbon triple bond. A “CM alkyl” denotes an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g. , n-propyl or isopropyl), or butyl (e.g., n-butyl, isobutyl, sec-butyl, or tert-butyl). Unless defined otherwise, the term “alkyl” preferably refers to CM alkyl, more preferably to methyl or ethyl, and even more preferably to methyl.

[0556] As used herein, the term “alkenyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. The term “C2-5 alkenyl” denotes an alkenyl group having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-

[0557] 1-en-1-yl, prop-1 -en-2-yl, or prop-2-en-1-yl), butenyl, butadienyl (e.g., buta-1 ,3-dien-1-yl or buta-1 ,3-dien-

[0558] 2-yl), pentenyl, or pentadienyl (e.g., isoprenyl). Unless defined otherwise, the term “alkenyl” preferably refers to C2-4 alkenyl.

[0559] As used herein, the term “alkynyl” refers to a monovalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon-to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. The term “C2-5 alkynyl” denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl), or butynyl. Unless defined otherwise, the term “alkynyl” preferably refers to C2- 4 alkynyl.

[0560] As used herein, the term “alkylene” refers to an alkanediyl group, i.e. a divalent saturated acyclic hydrocarbon group which may be linear or branched. A “CM alkylene” denotes an alkylene group having 1 to 5 carbon atoms, and the term “C0-3 alkylene" indicates that a covalent bond (corresponding to the option “Co alkylene”) or a C1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (- CH2-), ethylene (e.g., -CH2-CH2- or -CH(-CH3)-), propylene (e.g., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, -CH2- CH(-CH3)-, or -CH(-CH3)-CH2-), or butylene (e.g., -CH2-CH2-CH2-CH2-). Unless defined otherwise, the term “alkylene” preferably refers to CM alkylene (including, in particular, linear CM alkylene), more preferably to methylene or ethylene, and even more preferably to methylene.

[0561] As used herein, the term “alkenylene” refers to an alkenediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon- Ill to-carbon double bonds while it does not comprise any carbon-to-carbon triple bond. A “C2-5 alkenylene’ denotes an alkenylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkenylene’ preferably refers to C2-4 alkenylene (including, in particular, linear C2-4 alkenylene).

[0562] As used herein, the term “alkynylene” refers to an alkynediyl group, i.e. a divalent unsaturated acyclic hydrocarbon group which may be linear or branched and comprises one or more (e.g., one or two) carbon- to-carbon triple bonds and optionally one or more (e.g., one or two) carbon-to-carbon double bonds. A “C2-5 alkynylene” denotes an alkynylene group having 2 to 5 carbon atoms. Unless defined otherwise, the term “alkynylene” preferably refers to C2.4 alkynylene (including, in particular, linear C2-4 alkynylene).

[0563] As used herein, the term “carbocyclyl” refers to a hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless defined otherwise, “carbocyclyl” preferably refers to aryl, cycloalkyl or cycloalkenyl.

[0564] As used herein, the term “heterocyclyl” refers to a ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings), wherein said ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring comprised in said ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. Unless defined otherwise, “heterocyclyl” preferably refers to heteroaryl, heterocycloalkyl or heterocycloalkenyl.

[0565] As used herein, the term “aryl” refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Aryl” may, e.g., refer to phenyl, naphthyl, dialinyl (i.e., 1 ,2-dihydronaphthyl), tetralinyl (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indeny) (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H- fluorenyl, or azulenyl. Unless defined otherwise, an “aryl” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0566] As used herein, the term “arylene” refers to an aryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic). “Arylene” may, e.g., refer to phenylene (e.g., phen-1 ,2-diyl, phen-1 ,3-diyl, or phen-1 ,4-diyl), naphthylene (e.g., naphthalen-1 ,2-diyl, naphthalen-1 ,3-diyl, naphthalen-1 ,4-diyl, naphthalen-1 ,5-diyl, naphthalen-1 ,6- diyl, naphthalen-1, 7-diyl, naphthalen-2,3-diyl, naphthalen-2,5-diyl, naphthalen-2,6-diyl, naphthalen-2,7- diyl, or naphthalen-2,8-diyl), 1 ,2-dihydronaphthylene, 1 ,2,3,4-tetrahydronaphthylene, indanylene, indenylene, anthracenylene, phenanthrenylene, 9H-fluorenylene, or azulenylene. Unless defined otherwise, an “arylene” preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly phen- 1 ,4-diyl).

[0567] As used herein, the term “heteroaryl” refers to an aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heteroaryl” may, e.g., refer to thienyl (i.e., thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl (i.e., furanyl), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1- benzopyranyl or 4H-1 -benzopyranyl), isochromenyl (e.g., 1 H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1 H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridinyl; e.g., 2-pyridyl, 3- pyridyl, or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl (e.g., [1 ,10]phenanthrolinyl, [1 ,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl (i.e., furazanyl), or 1 ,3,4-oxadiazolyl), thiadiazolyl (e.g., 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, or 1 ,3,4-thiadiazolyl), phenoxazinyl, pyrazolo[1 ,5-a]pyrimidinyl (e.g., pyrazolo[1 ,5-a]pyrimidin-3-yl), 1 ,2-benzoisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo[b]thiophenyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1 ,2,3-triazolyl, 1 H-1 ,2,4-triazolyl, or 4H-1 ,2,4-triazolyl), benzotriazolyl, 1 H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, or 1 ,3,5-triazinyl), furo[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1 ,3-dihydrofuro[3,4- c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1 ,3-benzodioxolyl, benzodioxanyl (e.g., 1 ,3-benzodioxanyl or 1 ,4-benzodioxanyl), or coumarinyl. Unless defined otherwise, the term “heteroaryl” preferably refers to a 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroaryl” refers to a 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0568] As used herein, the term “heteroarylene” refers to a heteroaryl group, as defined herein above, but having two points of attachment, i.e. a divalent aromatic ring group, including monocyclic aromatic rings as well as bridged ring and / or fused ring systems containing at least one aromatic ring (e.g., ring systems composed of two or three fused rings, wherein at least one of these fused rings is aromatic; or bridged ring systems composed of two or three rings, wherein at least one of these bridged rings is aromatic), wherein said aromatic ring group comprises one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e. , to form an oxo group). For example, each heteroatom-containing ring comprised in said aromatic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. "Heteroarylene” may, e.g., refer to thienylene (i.e., thiophenylene; e.g., thien-2,3-diyl, thien-2,4-diyl, or thien-2,5-diyl), benzo[b]thienylene, naphtho[2,3-b]thienylene, thianthrenylene, furylene (i.e., furanylene; e.g., furan-2,3-diyl, furan-2,4-diyl, or furan-2,5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, chromenylene, isochromenylene, chromonylene, xanthenylene, phenoxathiinylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolylene, indolizinylene, purinylene, quinolylene, isoquinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, cinnolinylene, pteridinylene, carbazolylene, (3-carbolinylene, phenanthridinylene, acridinylene, perimidinylene, phenanthrolinylene, phenazinylene, thiazolylene (e.g., thiazol-2,4-diyl, thiazol-2,5-diyl, or thiazol-4,5-diyl), isothiazolylene (e.g., isothiazol-3,4-diyl, isothiazol-3,5-diyl, or isothiazol-4,5-diyl), phenothiazinylene, oxazolylene (e.g., oxazol-2,4-diyl, oxazol-2,5-diyl, or oxazol-4,5-diyl), isoxazolylene (e.g., isoxazol-3,4-diyl, isoxazol-3,5-diyl, or isoxazol-4,5-diyl), oxadiazolylene (e.g., 1 ,2,4-oxadiazol-3,5-diyl, 1 ,2,5-oxadiazol-3,4-diyl, or 1 ,3,4- oxadiazol-2,5-diyl), thiadiazolylene (e.g., 1 ,2,4-thiadiazol-3,5-diyl, 1 ,2,5-thiadiazol-3,4-diyl, or 1,3,4- thiadiazol-2,5-diyl), phenoxazinylene, pyrazolo[1 ,5-a]pyrimidinylene, 1 ,2-benzoisoxazolylene, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazolylene, benzimidazolylene, benzo[b]thiophenylene (i.e., benzothienylene), triazolylene (e.g., 1 H-1 ,2,3-triazolylene, 2H-1,2,3- triazolylene, 1 H-1 ,2,4-triazolylene, or 4H-1 ,2,4-triazolylene), benzotriazolylene, 1 H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1 ,2,3-triazinylene, 1 ,2,4-triazinylene, or 1 ,3,5-triazinylene), furo[2,3- c]pyridinylene, dihydrofuropyridinylene (e.g., 2,3-dihydrofuro[2,3-c]pyridinylene or 1 ,3-dihydrofuro[3,4-c]pyridinylene), imidazopyridinylene (e.g., imidazo[1 ,2-a]pyridinylene or imidazo[3,2-a]pyridinylene), quinazolinylene, thienopyridinylene, tetrahydrothienopyridinylene (e.g., 4,5,6,7-tetrahydrothieno[3,2-c] pyridinylene), dibenzofuranylene, 1 ,3-benzodioxolylene, benzodioxanylene (e.g., 1 ,3-benzodioxanylene or 1 ,4-benzodioxanylene), or coumarinylene. Unless defined otherwise, the term “heteroarylene” preferably refers to a divalent 5 to 14 membered (more preferably 5 to 10 membered) monocyclic ring or fused ring system comprising one or more (e.g,, one, two, three or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, a “heteroarylene” refers to a divalent 5 or 6 membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from 0, S, and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. A “heteroarylene”, including any of the specific heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from one another (in terms of the number of ring atoms separating them by the shortest possible connection) within one single ring or within the entire ring system of the corresponding heteroarylene.

[0569] As used herein, the term “cycloalkyl” refers to a saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkyl” may, e.g., refer to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decahydronaphthyl), or adamantyl. Unless defined otherwise, “cycloalkyl” preferably refers to a C3-11 cycloalkyl, and more preferably refers to a C3-7 cycloalkyl. A particularly preferred "cycloalkyl” is a monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropyl or cyclohexyl).

[0570] As used herein, the term “cycloalkylene” refers to a cycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings). “Cycloalkylene” may, e.g., refer to cyclopropylene (e.g., cyclopropan-1 ,1-diyl or cyclopropan-1 ,2-diyl), cyclobutylene (e.g., cyclobutan-1 ,1-diyl, cyclobutan-1 ,2-diyl, or cyclobutan-1 ,3-diyl), cyclopentylene (e.g., cyclopentan-1,1 -diyl, cyclopentan-1, 2-diyl, or cyclopentan- 1, 3-diyl), cyclohexylene (e.g., cyclohexan-1 ,1-diyl, cyclohexan-1 ,2-diyl, cyclohexan-1 ,3-diyl, or cyclohexan-1 ,4-diyl), cycloheptylene, decalinylene (i.e., decahydronaphthylene), or adamantylene. Unless defined otherwise, “cycloalkylene” preferably refers to a C3-11 cycloalkylene, and more preferably refers to a C3-7 cycloalkylene. A particularly preferred “cycloalkylene” is a divalent monocyclic saturated hydrocarbon ring having 3 to 7 ring members (e.g., cyclopropylene or cyclohexylene). As used herein, the term “heterocycloalkyl” refers to a saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g,, a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatomcontaining ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkyl” may, e.g., refer to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl (e.g., 1 ,4-diazepanyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholineyl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1 ,3-dioxolanyl, tetrahydropyranyl, 1 ,4-dioxanyl, oxepanyl, thiiranyl, thietanyl, tetrahydrothiophenyl (i.e., thiolanyl), 1 ,3-dithiolanyl, thianyl, 1 ,1-dioxothianyl, thiepanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl. Unless defined otherwise, “heterocycloalkyl” preferably refers to a 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkyl” refers to a 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0571] As used herein, the term “heterocycloalkylene” refers to a heterocycloalkyl group, as defined herein above, but having two points of attachment, i.e. a divalent saturated ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring comprised in said saturated ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkylene” may, e.g., refer to aziridinylene, azetidinylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidinylene, piperazinylene, azepanylene, diazepanylene (e.g., 1 ,4-diazepanylene), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxazepanylene, oxiranylene, oxetanylene, tetrahydrofuranylene, 1 ,3-dioxolanylene, tetrahydropyranylene, 1 ,4-dioxanylene, oxepanylene, thiiranylene , thietanylene, tetrahydrothiophenylene (i.e., thiolanylene), 1 ,3-dithiolanylene, thianylene, 1 ,1-dioxothianylene, thiepanylene, decahydroquinolinylene, decahydroisoquinolinylene, or 2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylene. Unless defined otherwise, “heterocycloalkylene” preferably refers to a divalent 3 to 11 membered saturated ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, “heterocycloalkylene" refers to a divalent 5 to 7 membered saturated monocyclic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0572] As used herein, the term “cycloalkenyl" refers to an unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to- carbon double bonds and does not comprise any carbon-to-carbon triple bond. “Cycloalkenyl” may, e.g., refer to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless defined otherwise, “cycloalkenyl" preferably refers to a C3-11 cycloalkenyl, and more preferably refers to a C3-7 cycloalkenyl. A particularly preferred “cycloalkenyl” is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g ., one or two; preferably one) carbon-to-carbon double bonds.

[0573] As used herein, the term “cycloalkenylene” refers to a cycloalkenyl group, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) hydrocarbon ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said hydrocarbon ring group comprises one or more (e.g., one or two) carbon-to- carbon double bonds and does not comprise any carbon-to-carbon triple bond.

[0574] As used herein, the term “heterocycloalkenyl” refers to an unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring. “Heterocycloalkenyl” may, e.g., refer to imidazolinyl (e.g., 2-imidazolinyl (i.e., 4,5-dihydro-1 H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), tetrahydropyridinyl (e.g., 1 ,2,3,6-tetrahydropyridinyl), dihydropyridinyl (e.g., 1 ,2- dihydropyridinyl or 2,3-dihydropyridinyl), pyranyl (e.g., 2H-pyranyl or 4H-pyranyl), thiopyranyl (e.g., 2H-thiopyranyl or 4H-thiopyranyl), dihydropyranyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazinyl, dihydroisoindolyl, octahydroquinolinyl (e.g., 1 ,2,3,4,4a,5,6,7-octahydroquinolinyl), or octahydroisoquinolinyl (e.g., 1 ,2,3,4,5,6,7,8-octahydroisoquinolinyl). Unless defined otherwise, “heterocycloalkenyl” preferably refers to a 3 to 11 membered unsaturated alicyclic ring group, which is a monocyclic ring or a fused ring system (e.g., a fused ring system composed of two fused rings), wherein said ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms; more preferably, “heterocycloalkenyl” refers to a 5 to 7 membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from 0, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms.

[0575] As used herein, the term “heterocycloalkenylene” refers to a heterocycloalkenyl group, as defined hereinabove, as defined hereinabove, but having two points of attachment, i.e. a divalent unsaturated alicyclic (non-aromatic) ring group, including monocyclic rings as well as bridged ring, spiro ring and / or fused ring systems (which may be composed, e.g., of two or three rings; such as, e.g., a fused ring system composed of two or three fused rings), wherein said ring group contains one or more (such as, e.g., one, two, three, or four) ring heteroatoms independently selected from 0, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein said ring group comprises at least one double bond between adjacent ring atoms and does not comprise any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring comprised in said unsaturated alicyclic ring group may contain one or two 0 atoms and / or one or two S atoms (which may optionally be oxidized) and / or one, two, three or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that there is at least one carbon ring atom (which may optionally be oxidized) in the corresponding heteroatom-containing ring.

[0576] As used herein, the term "halogen” refers to fluoro (-F) , chloro (-CI), bromo (-Br), or iodo (-I). As it is to be understood for the skilled person, the terms “halogen” and “halo” may be used interchangeably.

[0577] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms which are selected independently from fluoro, chloro, bromo and iodo, and are preferably all fluoro atoms. It will be understood that the maximum number of halogen atoms is limited by the number of available attachment sites and, thus, depends on the number of carbon atoms comprised in the alkyl moiety of the haloalkyl group. “Haloalkyl” may, e.g., refer to -CF3, -CHF2, -CH2F, -CF2-CH3, -CH2-CF3, -CH2-CHF2, -CH2-CF2-CH3, -CH2-CF2-CF3, or -CH(CF3)2. A particularly preferred “haloalkyl” group is -CF3.

[0578] The terms “bond” and “covalent bond” are used herein synonymously, unless explicitly indicated otherwise or contradicted by context.

[0579] As used herein, the terms “optional”, “optionally” and “may” denote that the indicated feature may be present but can also be absent. Whenever the term “optional”, “optionally” or “may" is used, the present invention specifically relates to both possibilities, i.e., that the corresponding feature is present or, alternatively, that the corresponding feature is absent. For example, the expression “X is optionally substituted with Y” (or “X may be substituted with Y”) means that X is either substituted with Y or is unsubstituted. Likewise, if a component of a composition is indicated to be “optional", the invention specifically relates to both possibilities, i.e., that the corresponding component is present (contained in the composition) or that the corresponding component is absent from the composition.

[0580] Various groups are referred to as being “optionally substituted” in this specification. Generally, these groups may carry one or more substituents, such as, e.g., one, two, three or four substituents. It will be understood that the maximum number of substituents is limited by the number of attachment sites available on the substituted moiety. Unless defined otherwise, the “optionally substituted” groups referred to in this specification carry preferably not more than two substituents and may, in particular, carry only one substituent. Moreover, unless defined otherwise, it is preferred that the optional substituents are absent, i.e. that the corresponding groups are unsubstituted.

[0581] A skilled person will appreciate that the substituent groups comprised in the compounds of the present invention may be attached to the remainder of the respective compound via a number of different positions of the corresponding specific substituent group. Unless defined otherwise, the preferred attachment positions for the various specific substituent groups are as illustrated In the examples.

[0582] As used herein, unless explicitly indicated otherwise or contradicted by context, the terms “a”, “an” and “the” are used interchangeably with “one or more” and “at least one”. Thus, for example, a composition comprising “a” compound of formula (I) can be interpreted as referring to a composition comprising “one or more” compounds of formula (I). As understood herein, the term “peptide linker" refers preferably to a bivalent moiety obtained from a peptide, as defined herein, through attachment to -CO- moiety of its C-terminal amino acid residue and attachment to -NH- moiety of its N-terminal amino acid residue.

[0583] As understood herein, the term “peptide" refers to a polymer of two or more amino acid residues linked via amide bonds that are formed between an amino group of one amino acid residue and a carboxylic acid group of another amino acid residue. The amino acid residues comprised in the peptide or protein, which are also referred to as amino acids, may be selected from the 20 standard proteinogenic a amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) but also from non-proteinogenic and / or non-standard a amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4 hydroxyproline, a methylalanine (i.e., 2 aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, 2,4-diamino-3-hydroxybutyric acid (2,4-diamino- 3-hydroxybutyrate), 2,4-diaminobutyrate, 5-hydroxylysine, 3-hydroxyarginine, 2,3-didehydroarginine or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as p amino acids (e.g., p alanine), y-amino acids (e.g., y- aminobutyric acid, isoglutamine, or statine) and 5-amino acids. Preferably, the amino acid residues comprised in the peptide or protein are selected from a amino acids, more preferably from the 20 standard proteinogenic a amino acids (which can be present as the L isomer or the D-isomer, and are preferably all present as the L isomer). The peptide may be unmodified or may be modified, e.g., at its N terminus, at its C terminus and / or at a functional group in the side chain of any of its amino acid residues (particularly at the side chain functional group of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu, and / or Arg residues). Such modifications may include, e.g., the attachment of any of the protecting groups described for the corresponding functional groups in: Wuts PGM & Greene TW, Greene’s protective groups in organic synthesis, John Wiley & Sons, 2006. Such modifications may also include the covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide), the glycosylation and / or the acylation with one or more fatty acids (e.g., one or more C8-30 alkanoic or alkenoic acids; forming a fatty acid acylated peptide or protein). Moreover, such modified peptides or proteins may also include peptidomimetics, provided that they contain at least two amino acids that are linked via an amide bond (formed between an amino group of one amino acid and a carboxyl group of another amino acid). The amino acid residues comprised in the peptide or protein may, e.g., be present as a linear molecular chain (forming a linear peptide) or may form one or more rings (corresponding to a cyclic peptide). Unless indicated to the contrary, the peptides as referred to herein are linear peptides of less than 40 residues, comprising amino acid residues selected from the 20 standard proteinogenic a amino acids, each present as L isomer. Preferably, side chains of amino acid residues are not modified. Preferably, N-terminus of the peptide is either not modified or is acetylated, and / or C-terminus of the peptide is either not modified or is amidated. Acetylation is preferably understood herein as a modification of the amino group, preferably a main chain amino group NH2-, into CH3CONH- moiety. Amidation is preferably understood herein as a modification of the carboxylic group, preferably a main chain carboxylic group -COOH, into a -CONH2 moiety.

[0584] As used herein, the term “amino acid" refers, in particular, to any one of the 20 standard proteinogenic a-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Vai) but also to non-proteinogenic and / or non-standard a-amino acids (such as, e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, a-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, terleucine (tert-leucine), labionin, or an alanine or glycine that is substituted at the side chain with a cyclic group such as, e.g., cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine) as well as P-amino acids (e.g., 0-alanine), y-amino acids (e.g., y-aminobutyric acid, isoglutamine, or statine) and / or 5-amino acids as well as any other compound comprising at least one carboxylic acid group and at least one amino group. Unless defined otherwise, an “amino acid" preferably refers to an a-amino acid, more preferably to any one of the 20 standard proteinogenic a-amino acids (which can be present as the L-isomer or the D-isomer, and are preferably present as the L-isomer).

[0585] The terms “peptide”, “polypeptide” and “protein” may be used interchangeably. Moreover, unless explicitly indicated otherwise or contradicted by context, any reference to a sequence (or partial sequence) from a defined amino acid sequence (e.g., defined by its SEQ ID) is to be understood as relating to a continuous sequence (or a continuous partial sequence) from the corresponding defined sequence. Thus, for example, any reference to a partial sequence of X to Y amino acid residues from a larger amino acid sequence defined by its SEQ ID is to be understood as relating to a continuous (uninterrupted) sequence of X to Y amino acid residues from the defined larger amino acid sequence.

[0586] The term “% sequence identity”, as used herein, e.g., in connection with amino acid sequences of proteins / peptides and / or in connection with nucleotide sequences of nucleic acid molecules, describes the number of matches of identical amino acid residues (or nucleotides) of two or more aligned sequences as compared to the number of amino acid residues (or nucleotides) making up the overall length of the compared sequences (or the overall compared portions thereof). Using an alignment of two or more sequences or subsequences, the percentage of amino acid residues (or nucleotides) that are the same may be determined when the (sub)sequences are compared and aligned for maximum correspondence over a window of comparison, or over a designated region as measured using a sequence comparison algorithm as known in the art, or when manually aligned and visually inspected. Examples of algorithms that can be used for determining sequence identity include, in particular, those based on the NCB I BLAST algorithm (Altschul SF et al., Nucleic Acids Res, 1997, 25(17): 3389-402, doi: 10.1093 / nar / 25.17.3389), CLUSTALW (Thompson JD et al., Nucleic Acids Res, 1994, 22(22): 4673-80, doi: 10.1093 / nar / 22.22.4673), or FASTA (Pearson WR et al., Proc Natl Acad Sci USA, 1988, 85(8): 2444-8, doi: 10.1073 / pnas.85.8.2444). Although the FASTA algorithm typically does not consider internal nonmatching deletions or additions in sequences, i.e. gaps, in its calculation, this can be corrected manually to avoid an overestimation of the % sequence identity. CLUSTALW, however, does take sequence gaps into account in its identity calculations.

[0587] Furthermore, it is to be understood that wherever a numerical range is provided / described herein, all values and subranges encompassed by the respective numerical range are specifically provided by the invention. Accordingly, the present invention specifically and individually relates to each value that falls within a numerical range described herein, as well as each and any subrange encompassed by a numerical range described herein.

[0588] As used herein, the term “about” preferably refers to ±10% of the indicated numerical value, more preferably to ±5% of the indicated numerical value, and in particular to the exact numerical value indicated. If the term “about” is used in connection with the endpoints of a range, it preferably refers to the range from the lower endpoint -10% of its indicated numerical value to the upper endpoint +10% of its indicated numerical value, more preferably to the range from of the lower endpoint -5% to the upper endpoint +5%, and even more preferably to the range defined by the exact numerical values of the lower endpoint and the upper endpoint. If the term “about” is used in connection with the endpoint of an open- ended range, it preferably refers to the corresponding range starting from the lower endpoint -10% or from the upper endpoint +10%, more preferably to the range starting from the lower endpoint -5% or from the upper endpoint +5%, and even more preferably to the open-ended range defined by the exact numerical value of the corresponding endpoint. If the term “about” is used in connection with a parameter that is quantified in integers, such as the number of nucleotides in a given nucleic acid or the number of amino acid residues in a given peptide or protein, the numbers corresponding to ±10% or ±5% of the indicated numerical value are to be rounded to the nearest integer (using the tie-breaking rule "round half up”). Thus, for example, the expression "about 25 amino acid residues” preferably refers to the range of 23 to 28 amino acid residues, more preferably to the range of 24 to 26 amino acid residues, and even more preferably refers to the specific value of 25 amino acid residues.

[0589] As used herein, the term “comprising” (or “comprise”, “comprises”, “contain”, “contains”, or “containing”), unless explicitly indicated otherwise or contradicted by context, has the meaning of “containing, inter alia", i.e., “containing, among further optional elements, ...”. In addition, this term also includes the narrower meanings of “consisting essentially of’ and “consisting of’. For example, the term “A comprising B and C” has the meaning of “A containing, inter alia, B and C", wherein A may contain further optional elements (e.g., “A containing B, C and D” would also be encompassed), but this term also includes (i.e., also provides a specific disclosure of) the meaning of “A consisting essentially of B and C” and the meaning of “A consisting of B and C” (i.e., no other components than B and C are comprised in A).

[0590] As used herein, the term “having” (or “has” or “have”), particularly when used in connection with an amino acid sequence or a nucleotide sequence, means “comprising”. In addition, the term "having” also includes the preferred meaning “consisting of”. Accordingly, an expression such as, e.g., “a VH domain having the sequence...” indicates that the VH domain “comprises” the indicated sequence, and that it preferably “consists of’ the indicated sequence.

[0591] Unless specifically indicated otherwise or contradicted by context, all properties and parameters (including functional parameters) referred to herein are preferably to be determined (and, likewise, all assays and tests referred to herein are preferably to be conducted) at standard conditions, particularly at standard ambient temperature and pressure conditions, e.g., at a temperature of 25°C (298.15 K) and at an absolute pressure of 101.325 kPa (1 atm). Assays determining a biological activity (e.g., an enzymatic activity) can also be conducted at a temperature of 37°C.

[0592] Moreover, unless indicated otherwise, any reference to a database, an industry standard, a pharmacopeia, or a manufacturer’s manual refers to the corresponding latest version that was available either at the filing date or at the earliest priority date (which may also be referred to as the earliest filing date) of the present specification, preferably the latest version that was available at the earliest priority date of the present specification. All amino acid sequences referred to herein are also described in a concurrently filed sequence listing, which is incorporated herein by reference in its entirety. In the case of conflict between any sequence specified in the present disclosure and the corresponding sequence specified in the accompanying sequence listing, the present invention specifically and individually relates to each one of the respective sequences.

[0593] It is to be understood that the present invention specifically and individually relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. Thus, in accordance with the present invention, each such combination is specifically envisaged herein.

[0594] In a further embodiment, the present invention relates to a pharmaceutical composition comprising the immunoconjugate of the present invention, and a pharmaceutically acceptable carrier

[0595] Pharmaceutical formulations of an immunoconjugate of the present invention as described herein are prepared by mixing such immunoconjugate having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA or GLDA; sugars such as sucrose, mannitol, trehalose or sorbitol; osmo-protectants like ectoin; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.), Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in US Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

[0596] The term "pharmaceutical formulation" or “pharmaceutical composition” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0597] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0598] Exemplary lyophilized immunoconjugate formulations are described in US Patent No. 6,267,958, Aqueous immunoconjugate formulations include those described in US Patent No. 6,171 ,586 and W0 2006 / 044908, the latter formulations including a histidine-acetate buffer.

[0599] The formulation herein may also contain more than one active ingredient as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other.

[0600] Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol. A. Ed. (1980).

[0601] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody or immunoconjugate, which matrices are in the form of shaped articles, e.g. films, or microcapsules. The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

[0602] In one embodiment, the present invention relates to the immunoconjugate of the present invention or pharmaceutical composition of the present invention for use as a medicament. In other words, the present invention relates to the immunoconjugate of the present invention or pharmaceutical composition of the present invention for use in therapy. It is to be understood that the immunoconjugate or the pharmaceutical compositions of the present invention can be used in the treatment of a disease or a disorder.

[0603] As used herein, "treatment" (and grammatical variations thereof such as "treat" or "treating") refers to clinical intervention in an atempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, immunoconjugates of the invention are used to delay development of a disease or to slow the progression of a disease.

[0604] An immunoconjugate of the invention (and any additional therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional, intrauterine or intravesical administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, e.g. by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.

[0605] Immunoconjugates of the invention would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The immunoconjugate need not be, but is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of immunoconjugate present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically / clinically determined to be appropriate.

[0606] For the prevention or treatment of disease, the appropriate dosage of an immunoconjugate of the invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of immunoconjugate, the severity and course of the disease, whether the immunoconjugate is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the immunoconjugate, and the discretion of the attending physician. The immunoconjugate is suitably administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 pg / kg to 15 mg / kg (e.g. 0.1 mg / kg-10 mg / kg) of immunoconjugate can be an initial candidate dosage for administration to the patient, whether, for example, by one or more separate administrations, or by continuous infusion. One typical daily dosage might range from about 1 pg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the immunoconjugate would be in the range from about 0.05 mg / kg to about 10 mg / kg. Thus, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, e.g. every week or every three weeks (e.g. such that the patient receives from about two to about twenty, or e.g. about six doses of the antibody). An initial higher loading dose, followed by one or more lower doses may be administered. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques an...

Claims

1. CLAIMS1 . An immunoconjugate comprising a) an antibody, an antibody fragment, an antibody construct, and / or a binding moiety binding to a tumor antigen and / or to a cancer antigen, whereby said tumor antigen and / or to said cancer antigen is preferably displayed on the surface of a cancer cell; and b) a compound according to formula (I):whereinR1is selected from -H, C1-5 alkyl, -OH, -CN and -NO2;R2is selected from -H, halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -CN, -NO2, -CHO, -COOH, -COO(Ci- 5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(Ci_5alkyl);R3is selected from -H, halogen, C1.5 alkyl, aryl, -OH, -0(C1-5 alkyl), -CN, -N02, -NH2, -NH(Ci-s alkyl), -N(C1-5 aikyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -C0NH(Ci-5alkyl), - CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(Ci-5alkyl);R4is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(C1-5 alkyl), -N(Ci-s alkyl)(Ci- 5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -C0NH(C1-5 alkyl), -CON(C1-5 alkyl)(Ci-5alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl);R5is selected from -H, halogen, C1-5 alkyl, aryl, -CN, -NO2, -NH2, -NH(CI-5 alkyl), -N(CI-5 alkyl)(Ci- 5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(Ci.salkyl)(Ci-5alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(C1-5 alkyl); andA is a phenyl or five- or six-membered heteroaryl, optionally substituted with one or more groups selected from Rs; and each Rsis independently selected from halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, -O(Ci-s alkyl), -(C1- 5 alkylene)-OH, -CN, -NH2, -(C1-5 alkylene)-NH2, -(C1-5 alkylene)-NH(C1-5 alkyl), -(C1-5 alkylene)- N(CI-5 alkyl)(C1-5 alkyl), -O-(C1-5 alkylene)-N H2, -O-(C2-5 alkylene)-N H(C1-5 alkyl), -O-(C2-5 alkylene)- N(C1-5 alkyl)(C1-5 alkyl), -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci.5alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and - SO2N(C1-5 alkyl)(C1-5 alkyl).

2. The immunoconjugate of claim 1, wherein said tumor cell and / or said cancer cell is selected from a neuroblastoma cell, an Ewing sarcoma cell, an osteosarcoma cell, brain cancer cell, a medulloblastoma cell, a glioma cell, a leukemia cell, a rhabdomyosarcoma cell, a melanoma cell, a breast cancer cell, a triple negative breast cancer cell, a colorectal cancer cell, a colorectal adenoma cell, a lung cancer cell, , an ovarian cancer cell, a multiple myeloma cell, a hepatocellular carcinoma cell, pancreatic cancer cell, prostate cancer cell, bladder cancer cell, urethral cancer cell, cervical cancer cell, a soft tissue sarcoma cell and a lymphoma cell.

3. The immunoconjugate of claim 1 or 2, wherein said tumor cell and / or said cancer cell is selected from a neuroblastoma cell, an Ewing sarcoma cell, an osteosarcoma cell, a brain cancer cell, a leukemia cell, a rhabdomyosarcoma cell, a melanoma cell and a triple negative breast cancer cell.

4. The immunoconjugate of any one of claims 1 to 3, wherein said cancer cell is a neuroblastoma cell or a brain cancer cell, in particular, a medulloblastoma cell or a glioma cell; wherein said cancer cell is a leukemia cell, in particular an acute myeloid leukemia cell (AML cell) or a B-cell acute lymphoblastic leukemia cell (B-ALL cell); wherein said cancer cell is a melanoma cell; or wherein said cancer cell is a colorectal cancer cell, in particular a colorectal adenoma cell.

5. The immunoconjugate of any one of claims 1 to 4, wherein said tumor antigen and / or cancer antigen is selected from GD2, O-acetyl-GD2 (such as 7-O-acetyl-GD2 or 9-O-acetyl-GD2), B7-H3, CD33, GPC2, ALK, Trop-2, CD123, CLL-1 , STEAP1 , c-KIT, HER2, HER3, EGFR, FR-a and MUC16.

6. The immunoconjugate of any one of claims 1 to 5, wherein said tumor antigen is selected from GD2, O-acetyl-GD2, B7-H3, GPC2, and ALK.

7. The immunoconjugate of claim 6, wherein said tumor antigen and / or cancer antigen is GD2.

8. The immunoconjugate of any one of claims 1 to 7, wherein said antibody, antibody fragment, antibody construct, and / or binding moiety as recited in claim 1 (a) specifically binds GD2.

9. The immunoconjugate of any one of claims 5 to 7, wherein said antibody is selected from the group consisting of dinutuximab beta, dinutuximab and naxitamab; wherein said antibody fragment is an antigen-binding fragment of an antibody selected from the group consisting of dinutuximab beta, dinutuximab and naxitamab; and / or wherein said antibody construct comprises an antigen-binding fragment of an antibody selected from the group consisting of dinutuximab beta, dinutuximab and naxitamab,10. The immunoconjugate of any one of claims 1 to 5, wherein said cancer antigen is CD33.11 . The immunoconjugate of any one of claims 1 to 5, or 10, wherein said antibody, antibody fragment, antibody construct, and / or binding moiety as recited in claim 1 (a)) specifically binds CD33.

12. The immunoconjugate of claim 10 or 11 , wherein said antibody is gemtuzumab; wherein said antibody fragment is an antigen-binding fragment of gemtuzumab; and / or wherein said antibody construct comprises an antigen-binding fragment of gemtuzumab.

13. The immunoconjugate of any one of claims 1 to 12, wherein the immunoconjugate comprises a moiety according to formula (II):-LI-L.P-L.2-X-(II) whereinLi is C2-20 alkylene, optionally substituted with one or more substituents selected from -ON, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may independently be replaced by a group selected from -CH=CH-, -C=C-, -O-, -NR'-, -CO-, Ce-io arylene, 5-6 membered heteroarylene, -(CH2-O-CH2)-, -(CH2-CH2-O)-, -CO-O-, -CO-NR'-, C3-C11 cycloalkylene, or 4-11 membered heterocycloalkylene, wherein R’ is H or Ci-Ce alkyl;LP is a bond or is a peptide linker which includes up to 5 amino acid residues, wherein the C- terminus of the peptide linker is connected to -NH- moiety of L2 or to X,L2 is -NH-1,4-phenylene-CH2- or is a bond, andX is selected from a bond, -O-, -O-CO-, -CO-O-, -O-CO-NH-, -O-CO-NH-CH2- and -NH-, wherein X is attached to the compound of formula (I).

14. The immunoconjugate of claim 13, wherein Li is C2-12 alkylene, optionally substituted with one or more substituents selected from -CN, halogen, -OH, and -NH2, and wherein one or more -CH2- groups may independently be replaced by a group selected from -O-, -NR’-, -CO-, -(CH2-O-CH2)- , -(CH2-CH2-O)-, C3-C11 cycloalkylene, and 4-11 membered heterocycloalkylene, wherein R’ is H or CrCe alkyl, wherein the right empty valence of Li is attached to Lp.

15. The immunoconjugate of claim 14, wherein Li is selected from:wherein the right empty valence of Li is attached to Lp16. The immunoconjugate of claim 15, wherein the Li is:preferably wherein the Li iswherein the right empty valence of Li is attached to LP17. The immunoconjugate of claim 15, wherein the Li iswherein the right empty valence of Li is attached to LP.

18. The immunoconjugate of any one of claims 13 to 17, wherein Lp is selected from -Val-Cit-, -cBu- Cit-, -Val-Ala-, -Glu-Val-Cit-, -Gly-Gly-Gly-, -Ala-Ala-Asn- and -Gly-Gly-Phe-Gly- (SEQ ID NO.: 28), wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2or to X, and wherein the N-terminus is connected to Li .

19. The immunoconjugate of claim 18, wherein Lp is -Gly-Gly-Phe-Gly- (SEQ ID NO.: 28), wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2or to X, and wherein the N- terminus is connected to Li.

20. The immunoconjugate of claim 18, wherein the peptide linker is -Val-Cit-, wherein the C-terminus of the peptide linker is connected to -NH- moiety of L2or to X, and wherein the N-terminus is connected to Li.21 . The immunoconjugate of any one of claims 13 to 20, wherein X is -O-CO-, wherein the right empty valence of said -O-CO- is attached to the compound of formula (I).

22. The immunoconjugate of any one of claims 13 to 20, wherein X is a bond.

23. The immunoconjugate of any one of claims 13 to 20, wherein X is -O-CO-NH-CH2-, wherein the right empty valence of said -O-CO-NH-CH2- is attached to the compound of formula (I).

24. The immunoconjugate of any one of claims 13 to 23, wherein the moiety of formula (II) is comprised in a moiety of formula (Ila):-Z-LI-LP-L2-X-(Ila) whereinattached through its right empty valence to Li, and through its left empty valence to a cysteine residue of the antibody, andwherein Li, Lp, L.2, and X are as defined in any one of claims 13 to 23.

25. The immunoconjugate of any one of claims 1 to 24, wherein R1is -H or -OH, preferably wherein R1is -H.

26. The immunoconjugate of any one of claims 1 to 25, wherein R2is selected from -H, halogen, -OH, -CN, -CONH2, -CONH(CI-5 alkyl), and -CON(CI-5 alkyl)(C1-5 alkyl), preferably wherein R2is -H, halogen or -CN, more preferably wherein R2is -CN.

27. The immunoconjugate of any one of claims 1 to 26, wherein R3is selected from -H, halogen, and C1-5 alkyl, preferably wherein R3is selected from -H and C1-5 alkyl, more preferably wherein R3is selected from -H and methyl.

28. The immunoconjugate of any one of claims 1 to 27, wherein R4is selected from -H and halogen, preferably wherein R4is -H.

29. The immunoconjugate of any one of claims 1 to 28, wherein R5is selected from -H and halogen, preferably wherein R5is -H.

30. The immunoconjugate of any one of claims 1 to 29, wherein A is phenyl or is a five- or sixmembered heteroaryl and wherein said phenyl or said five- or six-membered heteroaryl is optionally substituted with one or more groups selected from -H, halogen, C1-5 alkyl, C1-5 haloalkyl, -OH, - O(C1-5 alkyl), -CN, -NO2, -NH(C1-5 alkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(Ci-5alkyl), -CONH2, -CONH(C1-5 alkyl), -CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and - SO2N(C1-5 alkyl)(C1-5 alkyl), preferably said phenyl substituted with methyl or a phenyl substituted with -CN.31 . The immunoconjugate of any one of claims 1 to 30, wherein the compound of formula (I) is selected from the group consisting of:preferably selected from the group consisting of:

32. The immunoconjugate of any one of claims 1 to 31 , wherein the compound of formula (I) is present in the immunoconjugate as a moiety of formula (la):wherein R1, R2, R3, R4, R5and A are as defined in any one of claims 1 to 30, preferably wherein X is a bond.

33. The immunoconjugate of claim 32, wherein the moiety of formula (la) is a moiety of formula (la-1):(la-1).

34. The immunoconjugate of claim 32, wherein the compound of formula (I) is present in the immunoconjugate as a moiety of formula (lb):preferably(lb-1) wherein R1, R2, R3, R4, and R5are as defined in any one of claims 1 to 10, preferably wherein X is -O-CO-, wherein the right empty valence of said -O-CO- is connected to the moiety of formula (lb), wherein Rsis selected from halogen, C1-5 alkyl, -OH, -O(C1-5 alkyl), -CN, -NO2, -NH(Ci-salkyl), -N(C1-5 alkyl)(C1-5 alkyl), -CHO, -COOH, -COO(C1-5 alkyl), -CONH2, -CONH(C1-5 alkyl), - CON(C1-5 alkyl)(C1-5 alkyl), -SO2NH2, -SO2NH(C1-5 alkyl) and -SO2N(C1-5 alkyl)(Ci-5alkyl), and wherein n is an integer from 0 to 4, preferably wherein the moiety of formula (lb) is a moiety of formula ( lb-2) :(lb-2)35. A pharmaceutical composition comprising the immunoconjugate of any one of claims 1 to 34, and a pharmaceutically acceptable carrier.

36. The immunoconjugate of any one of claims 1 to 34 or a pharmaceutical composition of claim 35 for use as a medicament.

37. The immunoconjugate of any one of claims 1 to 34 or a pharmaceutical composition of claim 35 for use In the treatment or prevention of a tumor and / or in the treatment or prevention of cancer.

38. A method of treatment and / or prevention of a tumor and / or of cancer, said method comprising a step of administering to a patient in need of such treatment and / or prevention the immunoconjugate of any one of claims 1 to 34, whereby said immunoconjugate is comprised in a pharmaceutical composition.

39. The immunoconjugate for use or the pharmaceutical composition for use of claim 37, or the method of claim 38, wherein said cancer is characterized by upregulation of RNA-binding motif protein 39 (RBM39).

40. The immunoconjugate for use or the pharmaceutical composition for use of claim 37 or 39, or the method of claim 38 or 39, wherein said cancer is selected from neuroblastoma, Ewing sarcoma, osteosarcoma, brain cancer (like medulloblastoma or glioma), acute myeloid leukemia (AML), B- cell acute lymphoblastic leukemia (B-ALL), rhabdomyosarcoma, melanoma, breast cancer, triple negative breast cancer, lung cancer, colorectal cancer, ovarian cancer, multiple myeloma, hepatocellular carcinoma, pancreatic cancer, and ovarian cancer.41 . The immunoconjugate for use or the pharmaceutical composition for use of any one of claims 37, 39, or 40, or the method of any one of claims 38 to 40, wherein said cancer is selected from neuroblastoma, Ewing sarcoma, osteosarcoma, brain cancer (like medulloblastoma or glioma), rhabdomyosarcoma, melanoma, acute myeloid leukemia (AML), breast cancer, triple negative breast cancer, and colorectal cancer.

42. The immunoconjugate for use or the pharmaceutical composition for use of any one of claims 37, or 39 to 41 , or the method of any one of claims 38 to 41, wherein the cancer is neuroblastoma, preferably pediatric neuroblastoma.

43. The immunoconjugate for use or the pharmaceutical composition for use of any one of claims 37 or 39 to 42, or the method of treatment of any one of claims 38 to 42, wherein the immunoconjugate or the pharmaceutical composition is to be co-administered with an EZH2 inhibitor (such as GSK126 or tazemetostat) or with an HDAC inhibitor (such as vorinostat, entinostat or panabinostat).

44. The immunoconjugate for use or the pharmaceutical composition for use of any one of claims 37, 39 or 40, or the method of any one of claims 38 to 40, wherein the cancer is leukemia, in particular acute myeloid leukemia.

45. A compound of formula:ZZ”LI-LP-L2-X-Y(III) or a pharmaceutically acceptable salt thereof, whereinZz is Zi or Z2,is C1-5 alkyl (such as methyl or ethyl), C2-5 alkenyl or C2-5 alkynyf (such as propargyl);Li , Lp, L2, and X are as defined in any one of claims 13 to 23; andY is the moiety of formula (la) or the moiety of formula (lb) as defined in any one of claims 32 to

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