Martin Treder

Trispecific antibodies for CD16A-directed NK cell engagement and dual-targeting of tumor cells

Bispecific antibodies that redirect the lytic activity of cytotoxic immune effector cells, such as T- and NK cells, onto tumor cells have emerged as a highly attractive and clinically validated treatment modality for hematological malignancies. Advancement of this therapeutic concept into solid tumor indications, however, is hampered by the scarcity of targetable antigens that are surface-expressed on tumor cells but demonstrate only limited expression on healthy tissues. To overcome this limitation, the concept of dual-targeting, i.e. the simultaneous targeting of two tumor-expressed surface antigens with limited co-expression on non-malignant cells, with multispecific antibodies has been proposed to increase tumor selectivity of antibody-induced effector cell cytotoxicity. Here, a novel CD16A (FcγRIIIa)-directed trispecific, tetravalent antibody format, termed aTriFlex, is described, that is capable of redirecting NK cell cytotoxicity to two surface-expressed antigens. Using a BCMA/CD200-based in vitro model system, the potential use of aTriFlex antibodies for dual-targeting and selective induction of NK cell-mediated target cell lysis was investigated. Bivalent bispecific target cell binding was found to result in significant avidity gains and up to 17-fold increased in vitro potency. These data suggest trispecific aTriFlex antibodies may support dual-targeting strategies to redirect NK cell cytotoxicity with increased selectivity to enable targeting of solid tumor antigens.

CD16A activation of NK cells promotes NK cell proliferation and memory-like cytotoxicity against cancer cells

Pre-activation via CD16A, a potent cytotoxicity receptor engaged by therapeutic bispecific antibodies, promoted NK cell proliferation and expansion. These CD16A-experienced NK cells exerted memory-like enhanced cytotoxicity and IFNγ production upon restimulation with tumor cells. CD16A is a potent cytotoxicity receptor on human natural killer (NK) cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2- and IL15-driven NK cell proliferation and expansion. This effect involved the upregulation of CD25 (IL2Rα) and CD132 (γc) on NK cells, resulting in increased sensitivity to low-dose IL2 or to IL15. CD16A engagement initially induced NK cell cytotoxicity. The lower NK cell reactivity observed 1 day after CD16A engagement could be recovered by reculture in IL2 or IL15. After reculture in IL2 or IL15, these CD16A-experienced NK cells exerted more vigorous IFNγ production upon restimulation with tumor cells or cytokines. Importantly, after reculture, CD16A-experienced NK cells also exerted increased cytotoxicity toward different tumor targets, mainly through the activating NK cell receptor NKG2D. Our findings uncover a role for CD16A engagement in priming NK cell responses to restimulation by cytokines and tumor cells, indicative of a memory-like functionality. Our study suggests that combination of AFM13 with IL2 or IL15 may boost NK cell antitumor activity in patients by expanding tumor-reactive NK cells and enhancing NK cell reactivity, even upon repeated tumor encounters. Cancer Immunol Res; 6(5); 517–27. ©2018 AACR.

Abstract 5671: AFM26 - A novel CD16A-directed bispecific TandAb targeting BCMA for multiple myeloma

Multiple myeloma (MM) is the second most common haematological cancer and is characterized by the accumulation of neoplastic plasma cells in the bone marrow and production of high levels of monoclonal immunoglobulin (M-protein). While historically considered incurable, recent approvals and ongoing clinical trials with monoclonal antibodies (mAbs) targeting surface antigens promise greatly improved outcomes and have heralded a new era of MM treatment in which immunotherapies are expected to take center stage. However, an unmet need remains as patients eventually relapse and/or become refractory to currently available treatments. Consequently, novel immunotherapeutic approaches are needed to provide improved treatment options to MM patients. Among the currently explored targets, B-cell maturation antigen (BCMA, CD269) is considered to be particularly attractive due to its limited expression on healthy tissues and almost universal expression on myeloma cells in the majority of patients. Natural killer (NK) cells are cytotoxic effectors of the innate immune system capable of rapidly eradicating infected and transformed cells. The cytolytic activity of NK-cells can be used therapeutically to induce tumor cell lysis by direct engagement of the activating receptor CD16A (FcγRIIIa) using mAbs (ADCC). Despite similar mechanisms of target cell lysis, activation of NK-cells is not associated with the systemic symptoms of high level cytokine release as seen with direct T-cell engagement. Hence, it is considered a potent immunotherapeutic approach with reduced toxicity and a well-manageable safety profile. NK-cells readily infiltrate bone marrow and are thought to contribute to the efficacy of current myeloma treatments. Therefore, redirecting NK-cell cytotoxicity to malignant plasma cells appears to be a suitable therapeutic approach for MM. Here we describe the characterization of AFM26, a novel tetravalent bispecific tandem diabody (TandAb) that specifically targets BCMA and CD16A with high affinity and induces potent and efficacious myeloma cell lysis. AFM26 incorporates an affinity-improved anti-CD16A domain and interacts bivalently with NK-cells, resulting in high avidity and prolonged cell surface retention that is largely unaffected by the presence of polyclonal IgG. Notably, AFM26 potently induces NK-cell-mediated in vitro lysis of target cells expressing low levels of BCMA at low effector:target ratios, even in presence of polyclonal IgG. This may suggest that AFM26, in contrast to classical mAbs, retains ADCC activity at low antibody concentrations in presence of serum IgG and despite high levels of IgG M-protein occurring in about half of MM patients. AFM26 exhibits high protein stability, full cross-reactivity with cynomolgus antigens (BCMA and CD16A) and does not bind APRIL and TACI, two functionally related receptors. These data suggest that TandAb AFM26 is a promising and highly potent drug candidate for MM treatment. Citation Format: Thorsten Gantke, Uwe Reusch, Kristina Ellwanger, Ivica Fucek, Michael Weichel, Martin Treder. AFM26 - A novel CD16A-directed bispecific TandAb targeting BCMA for multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5671. doi:10.1158/1538-7445.AM2017-5671

Highly Specific and Effective Targeting of EGFRvIII-Positive Tumors with TandAb Antibodies

To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb) antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR), and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving KDs in the picomolar range, and were used to construct a set of bispecific EGFRvIII-targeting TandAbs with a broad range of binding and cytotoxic properties. These antibodies exhibited an exquisite specificity for a distinguished epitope in the N-terminal portion of EGFRvIII, as shown on recombinant antigen in Western Blot, SPR, and ELISA, as well as on antigen-expressing cells in FACS assays, and did not bind to the wild-type EGFR. High-affinity EGFRvIII/CD3 TandAbs were most potent in killing assays, displaying cytotoxicity toward EGFRvIII-expressing CHO, F98 glioma, or human DK-MG cells with EC50 values in the range of 1–10 pM in vitro. They also demonstrated dose-dependent growth control in vivo in an EGFRvIII-positive subcutaneous xenograft tumor model. Together with the tumor-exclusive expression of EGFRvIII, the EGFRvIII/CD3 TandAbs’ high specificity and strictly target-dependent activation with no off-target activity provide an opportunity to target tumor cells and spare normal tissues, thereby reducing the side effects associated with other anti-EGFR therapies. In summary, EGFRvIII/CD3 TandAbs are highly attractive therapeutic antibody candidates for selective immunotherapy of EGFRvIII-positive tumors.

Abstract 3753: Identification of antibodies against a novel tumor-associated MHC/peptide-target and generation of highly specific and potent HLA-A*02MMP1-003/CD3 TandAbs

Tumor-associated antigens for effective and safe T-cell engagement are very limited, leaving a need to open up the therapeutic target space. Targeting disease-specific MHC/peptide complexes with bispecific T-cell-recruiting antibodies is a highly attractive strategy to address this need, but so far, generation of antibodies against these peptides has been reported to be challenging. Immatics’ unique target discovery engine XPRESIDENT ® holds the promise of identifying novel tumor-associated MHC/peptide complexes by providing direct and quantitative evidence for their presence on a large collection of primary human tumor and normal tissue specimens. By this approach, MMP1-003, an HLA-A*02-binding peptide originating from matrix metallopeptidase 1 (MMP1), was identified as a promising therapeutic target presented by several tumor types, including colorectal and lung cancer, but absent on normal tissues. These findings are underlined by RNAseq analysis of the source antigen which also points to MMP1 being a highly attractive tumor-associated target. Consequently, a fully human antibody phage display library was screened to identify highly specific single chain antibodies, which were shown to recognize the purified HLA-A*02/MMP1-003-complex in ELISA assays as well as on peptide-pulsed HLA-A*02 + T2 cells. The best candidates were reformatted into bispecific tetravalent TandAbs ® through Affimed´s proprietary platform using a human/cyno-cross-reactive CD3-binding domain for T-cell engagement. Specific target recognition was confirmed for the TandAbs in binding and cytotoxicity assays on peptide-pulsed T2 cells. HLA-A*02/peptide-complexes selected from the broad normal tissue immunopeptidome with a high degree of sequence similarity to the HLA-A*02/MMP1-003-complex served as controls to confirm the specificity and hence the low risk of off-target binding. The most promising candidates were tested on a panel of endogenously target-expressing cancer cell lines covering MMP1 +/- and HLA-A*02 +/- expression profiles, as well as the source proteins for the most closely related control peptides. The lead TandAb showed excellent target specificity across a wide range of peptide-pulsed and endogenously expressing cell lines as well as potent cytotoxicity with picomolar EC 50 . In summary, we have identified a tumor-associated MMP1-derived peptide in an HLA-A*02 context by exploiting the knowledge of tumor and healthy tissue immunopeptidomes using XPRESIDENT ® . Overcoming the existing barrier of developing antibodies targeting specific MHC/peptide complexes, we generated and characterized highly specific and potent T-cell-recruiting TandAbs. These hold the potential to open up the therapeutic target space for T-cell engagement by providing access to intracellular proteins that are presented in a disease-specific manner as MHC/peptide complexes. Citation Format: Toni Weinschenk, Erich Rajkovic, Uwe Reusch, Michael Weichel, Kristina Ellwanger, Ivica Fucek, Michael Tesar, Dominik Hinz, Vera Molkenthin, Sebastian Bunk, Norbert Hilf, Oliver Schoor, Dominik Maurer, Kerstin Mock, Carsten Reinhardt, Martin Treder. Identification of antibodies against a novel tumor-associated MHC/peptide-target and generation of highly specific and potent HLA-A*02 MMP1-003 /CD3 TandAbs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3753. doi:10.1158/1538-7445.AM2017-3753

Abstract 3641: EGFR/CD16A TandAbs are efficacious NK-cell engagers with favorable biological properties which potently kill EGFR+tumors with and without Ras mutation

Constitutive EGFR activation plays an important role in the pathophysiology of various solid cancers, such as colorectal cancer, non-small cell lung cancer or squamous cell carcinomas of the head and neck. Tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAbs), which interfere with signal transduction and activation of EGFR, are approved for treatment of such cancers. However, intrinsic or acquired resistance to these treatments has been described for many patients. Natural killer cells (NK-cells) are important effectors of innate immunity and NK-cell engagers have shown evidence of improved safety in patients compared to T-cell engagers. To specifically utilize the cytotoxic potential of NK-cells to eliminate EGFR-expressing tumors, we developed tetravalent bispecific EGFR/CD16A TandAbs comprising fully human Fv domains recognizing human and cynomolgus EGFR and CD16A. TandAbs recognizing epitopes in the extracellular domain of EGFR differing from epitopes targeted by other mAbs were characterized. Lead candidate AFM24 shows superior cytotoxicity in terms of ADCC (main mode of action) and reduced inhibition of EGFR-mediated phosphorylation compared to cetuximab. Importantly, inhibition of EGFR-signaling is believed to contribute to skin toxicity caused by therapeutic mAbs and TKI’s. AFM24’s cytotoxic activity was tested against EGFR+ tumor cell lines including some carrying a Ras mutation, which is a negative prognostic biomarker and renders cells less susceptible to cetuximab or panitumumab. The cetuximab-resistant CRC cell line HCT-116 or the NSCLC cell line A549 (both with Ras mutations) were efficiently killed with EGFR/CD16A TandAbs in vitro. In vivo data in the HCT-116 model indicate anti-tumor efficacy of AFM24, while no efficacy of cetuximab was seen. Importantly, AFM24 does not activate NK-cells without target cell binding and does not bind to any other members of the EGFR family. While binding and cytotoxic efficacy of many therapeutic mAbs are impaired by serum IgG, no substantial change in AFM24’s binding affinity to NK-cells was observed in the presence of high concentrations of human IgG. In calcein-release cytotoxicity assays with NK-cells as effectors, we showed that the presence of IgG had only little inhibitory effect on AFM24 efficacy compared to cetuximab. In addition, competition of an anti-CD16 mAb with AFM24 in cytotoxicity assays was substantially lower than with cetuximab. Taken together our data demonstrate that AFM24 is a highly potent human antibody displaying favorable biological properties over existing mAbs. This human/cynomolgus cross-reactive agent is currently in preclinical development to treat EGFR+ malignancies and has the potential to exhibit a favorable side effect profile and reduced toxicity and to overcome resistance to other targeted anti-EGFR therapeutic agents. Citation Format: Michael Kluge, Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Michael Weichel, Torsten Haneke, Stefan Knackmus, Joachim Koch, Martin Treder. EGFR/CD16A TandAbs are efficacious NK-cell engagers with favorable biological properties which potently kill EGFR+ tumors with and without Ras mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3641. doi:10.1158/1538-7445.AM2017-3641

Abstract 2997: The tetravalent bispecific antibody AFM13 engages and primes innate immune cells for anti-cancer immunity

AFM13 is a tetravalent bispecific antibody with bivalent binding to both CD30 and CD16A. It has been shown to engage NK-cells through CD16A with high affinity and specificity, resulting in strong NK-cell cytotoxicity, and is currently being tested in Phase 2 monotherapy and in combination with pembrolizumab in Phase 1b clinical trials. We have previously shown that AFM13-dependent activation of NK-cell cytotoxicity towards CD30+ tumor cells is more pronounced than that of anti-CD30 mAbs. In addition, AFM13 enhances NK-cell sensitivity to low doses of IL-2 and IL-15, leading to an increased NK-cell proliferative potential. Here, we have extended the panel of phenotypic markers on NK-cells that are modulated after exposure to CD30+ tumor cells in the presence of AFM13. Targeting some of these markers may enable the development of novel combination therapies. Moreover, we have analyzed the kinetics of NK-cell responses to AFM13 exposure. Even though short-term exposure to AFM13 significantly enhanced NK-cell cytotoxicity, long-term exposure led to a partial, transient functionally exhausted phenotype in vitro, which could be fully restored by cytokine stimulation for several days in the absence of AFM13. Importantly, these recovered cells displayed high cytotoxicity towards CD30+ target cells in the presence of AFM13. Interestingly, the transient NK-cell exhaustion was not related to the expression of typical exhaustion markers or insufficient levels of perforin and granzyme. These data may warrant the development of novel metronomic application regimens of AFM13. Further studies imply that immune cells other than NK-cells are able to inhibit growth of CD30+ tumor cells in an AFM13-dependent manner. This appears to be strictly dependent on CD16A and a specific cytokine milieu. Taken together, AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells, parameters that can be utilized to monitor NK-cell responses during AFM13 therapy. Moreover, based on our data, engagement of CD16A+ cells to the tumor site might enable several innate immune effector functions within the tumor microenvironment for synergistic anti-tumor activity. Citation Format: Jens Pahl, Joachim Koch, Uwe Reusch, Thorsten Gantke, Adelheid Cerwenka, Martin Treder. The tetravalent bispecific antibody AFM13 engages and primes innate immune cells for anti-cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2997. doi:10.1158/1538-7445.AM2017-2997

Abstract 593: Highly cytotoxic EGFR/CD16A TandAbs specifically recruit NK cells to potently kill various types of solid tumors

The effect on antigenicity of covalent attachment of lipid groups to a protein antigen was investigated. Coupling of palmitic acid to ovalbumin (OVA) enhanced major histocompatibility complex (MHC) class II-restricted presentation to most OVA-specific murine T-cell clones in vitro. The enhanced antigenicity of palmitoylated antigen was localized to the level of presentation of the synthetic peptide epitope, OVA 323-339. T-cell responses to palmitoylated antigen were more difficult to block with anti-MHC class II antibodies than responses to native antigen. However, T-cell proliferation to palmitoyl (p)-OVA and native (n)-OVA were blocked equally by anti-CD4 antibodies. Taken together, the results suggest that lipid conjugation of a protein antigen leads to the formation of a lipopeptide T-cell epitope with increased affinity of binding to MHC class II and/or T-cell receptor (TcR). These results have implications for the design of synthetic peptide vaccines.

Abstract 580: Anti-EGFRvIII TandAbs recruiting either T or NK cells are highly specific and potent therapeutic antibody candidates for the treatment of EGFRvIII+ tumors

EGFRvIII is the most prevalent tumor-specific variant of the wild-type EGFR and represents an attractive tumor target in various solid tumors such as GMB, HNSCC or NSCLC. Despite the clinical successes achieved with EGFR targeting antibodies or small molecule inhibitors little therapeutic progress has been made with EGFRvIII. There is still a high medical need in such cancers and several agents are in development to address this notoriously difficult target: Celldex′ vaccine rindopepimut in combination with bevacizumab in late-stage development, or ADCs in early development by Amgen or Abbvie. However, despite the high tumor specificity of EGFRvIII expression, no potent T- or NK-cell engaging are currently in clinical development. It has been recognized that there may be more therapeutic potential with bi-specific antibodies recruiting immune effectors for targeted destruction of antigen-positive tumor cells. We developed tetravalent, bi-specific TandAbs that recognize EGFRvIII, and recruiting either T-cells or NK-cells by binding to the activating receptors CD3 and CD16A, respectively. This targeted antibody approach allows the selective destruction of EGFRvIII+ tumor cells employing highly potent and efficacious immune effector cells whilst sparing normal cells that are EGFRvIII- or cells presenting the ubiquitously expressed EGFR. The selected EGFRvIII/CD3 and EGFRvIII/CD16A TandAbs exhibited exquisite specificity towards EGFRvIII in Western Blot, SPR, ELISA, and flow cytometric assays. No binding was observed to recombinant EGFR or to EGFR+ cells. They also displayed potent cytotoxicity towards EGFRvIII+ cell lines with EC50 values in the low picomolar range. No cytotoxicity was observed on EGFRvIII- target cells or cells expressing EGFR demonstrating the high selectivity of anti-EGFRvIII TandAbs. Importantly, in the absence of EGFRvIII+ target cells our TandAbs did not elicit T- or NK-cell activation and activation-induced immune cell proliferation suggesting an excellent safety profile. In vivo pharmacodynamics for anti-EGFRvIII TandAbs was demonstrated in a mouse xenograft model. The clinical relevance of EGFRvIII as a tumor marker and the binding of our anti-EGFRvIII variable domains were evaluated by immunohistochemistry. Binding was shown in glioblastoma and other solid tumors, but no expression was detectable on healthy tissue. In summary, the presented in vitro and in vivo studies qualify EGFRvIII/CD3 and EGFRvIII/CD16A TandAbs as highly attractive therapeutic antibody candidates and provides us with the possibility of employing both T-cell and NK-cell recruiting strategies for selective immunotherapy of EGFRvIII+ tumors. Due to tumor specific expression of EGFRvIII and the absence of off-target activity our TandAbs display an excellent safety profile reducing the risks of side effects associated with other anti-EGFRvIII therapies. Citation Format: Kristina Ellwanger, Uwe Reusch, Ivica Fucek, Michael Weichel, Thorsten Gantke, Stefan Knackmuss, Martin Treder. Anti-EGFRvIII TandAbs recruiting either T or NK cells are highly specific and potent therapeutic antibody candidates for the treatment of EGFRvIII+ tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 580.

Abstract 2323: Immune checkpoint inhibition by anti-PD-1 or CD137 co-stimulation enhances cytotoxicity towards CD30+ tumors mediated by the bispecific tetravalent CD30/CD16A TandAb AFM13

AFM13 is an NK-cell engaging CD30/CD16A bi-specific tetravalent TandAb antibody currently in Phase 2 clinical development in Hodgkin Lymphoma (HL) and CD30+ malignancies. Immune checkpoints inhibitors have demonstrated clinical efficacy in a variety of cancers, including HL. NK-cells are also regulated by a number of check-points, prompting us to investigate the combination of AFM13 with several immuno-modulatory antibodies. In previous experiments we were able to demonstrate higher efficacy of AFM13 than several immuno-modulatory antibodies in monotherapy and strong synergy between AFM13 and an anti-PD-1 antibody in vitro, as well as in vivo PDX models with human CD30+ HL tumors. In order to investigate the underlying immunological mechanisms we employed the same PDX model by implanting tumor fragments derived from surgical specimens of HL patients in immuno-deficient mice. After establishing tumors, mice were reconstituted with autologous patient-derived PBMC and treated with AFM13 alone and in combination with anti-PD-1 weekly for a total of three weeks. Tumor size, tumor-infiltrating human lymphocytes, myeloid cells and intra-tumoral cytokines were evaluated on days 30, 44, and 58, i.e. 2, 16 and 30 days after treatment start. While monotherapy with AFM13 was reproducibly more potent than anti-PD-1, significant synergy was observed when both agents were combined. Analysis of the tumors on day 58 revealed a strong correlation between tumor growth inhibition and levels of tumor-infiltrating NK-cells, T-cells, myeloid cells and intra-tumoral cytokines such as IFNg. In contrast to anti-PD-1 monotherapy, which only induced T-cell infiltration, AFM13 monotherapy was able to induce infiltration of NK- and T-cells in the tumors, however the combination further enhanced infiltration of both, NK- and T-cells. AFM13 resulted in stronger infiltration of macrophages than anti-PD-1, which was also increased by the combination of both agents, therefore further supporting cross-talk between innate and adaptive immunity. Furthermore, tumor analyses at earlier time-points (days 30 and 44) showed that the initial immune response is characterized by NK-cell infiltration and activation, as well as infiltration of macrophages, whilst the adaptive immune response by T-cells and activated dendritic cells was more pronounced on day 58. Combining AFM13 and anti-PD-1 augments infiltration and activation of all immune subpopulations. In conclusion, our data support strong synergistic anti-tumor efficacy when AFM13 is combined with anti-PD-1 checkpoint blockade in HL PDX models, mediated by tumor-infiltrating lymphocytes, macrophages and dendritic cells, and provide strong evidence for cross-talk between innate and adaptive immunity induced by AFM13-recruited human NK-cells. Citation Format: Xing Zhao, Narendiran Rajasekaran, Uwe Reusch, Jens-Peter Marschner, Martin Treder, Holbrook E. Kohrt. Immune checkpoint inhibition by anti-PD-1 or CD137 co-stimulation enhances cytotoxicity towards CD30+ tumors mediated by the bispecific tetravalent CD30/CD16A TandAb AFM13. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2323.