Sandra Berndt

Bayer · Immunooncology

Regulatory T cells (Tregs) are known to facilitate tumor progression by suppressing CD8+ T cells within the tumor microenvironment (TME), thereby also hampering the effectiveness of immune checkpoint inhibitors (ICIs). While systemic depletion of Tregs can enhance antitumor immunity, it also triggers undesirable autoimmune responses. Therefore, the...

Regulatory T cells (Tregs) play an indispensable role in mediating peripheral tolerance to self-antigens. They can also promote tumor growth by suppressing the function of effector CD8+ and CD4+ T cells in the tumor microenvironment (TME). Furthermore, Tregs are identified as one of the key resistance mechanisms hampering the efficacy of immune che...

Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a new mode of action for cancer-targeting antibody-drug conjugates (ADCs) with activity also in slowly proliferating cells. To extend the repertoire of available effector chemistries, we have developed a novel structural class of NAMPT inhibitors as ADC payloads....

Antibody–drug conjugates (ADCs) are used to target cancer cells by means of antibodies directed to tumor-associated antigens, causing the incorporation of a cytotoxic payload into target cells. Here, we characterized the mode of action of ADC costing of a TWEAKR-specific monoclonal antibody conjugated to a small molecule kinesin spindle protein (KS...

Background: Targeted thorium-227 conjugates (TTCs) are an emerging class of targeted alpha therapies (TATs). Their unique mode of action (MoA) is the induction of difficult-to-repair clustered DNA double-strand breaks. However, thus far, their effects on the immune system are largely unknown. Here, we investigated the immunostimulatory effects of...

p>Targeted thorium-227 conjugates (TTCs) represent a new class of targeted alpha therapy (TAT). TTCs consist of an antigen targeting moiety, which is covalently attached to a 3,2-HOPO chelator, enabling specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. TTCs have demonstrated potent preclinical in vivo acti...

Nicotinamide phosphoribosyl-transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway, generating nicotinamide adenine dinucleotide (NAD) from nicotinamide (NAM). Inhibition of intracellular NAMPT activity represents a differentiated mode-of-action for tumor-targeting antibody-drug conjugates (ADCs) as it is not dependent on cell proli...

Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a differentiated mode-of-action for tumor-targeting antibody-drug conjugates (ADCs) independent from cell proliferation. This opens up the possibility to target slowly growing tumors as well as resting antigen-positive tumor cells in addition to highly proliferati...

Introduction/ Purpose of study Targeting M2 macrophages as an immunosuppressive cell population within the tumor-microenvironment has become an important effort within preclinical research to achieve and enhance anti-tumor efficacy. In contrast to reprogramming approaches, we focused on effective and specific depletion of M2 macrophages (Mphs) by a...

Several antibody-drug conjugates (ADCs) have failed to achieve a sufficiently large therapeutic window in patients due toxicity induced by unspecific payload release in the circulation or ADC uptake into healthy organs. Herein, we describe the successful engineering of ADCs consisting of novel linkers, which are efficiently and selectively cleaved...

With the approval of meanwhile five ADCs and more than 80 ADCs in clinical trials, the ADC landscape has developed rapidly during the last decade. However, as indicated also by the large number of ADCs which failed in the clinic, it remains challenging to achieve a sufficiently large therapeutic window in cancer patients. Furthermore, the identific...

Chemotherapy and immune checkpoint inhibitors (ICIs) are approved for treatment of non-small-cell lung cancer (NSCLC). However, there still remains a high medical need in NSCLC, eg. in patients non-responsive to ICIs or progressed after treatment with ICIs. Mesothelin (MSLN) is expressed in ~60% of lung adenocarcinomas. Here, we describe the mesoth...

Inhibitors of kinesin spindle protein (KSP/Eg5) have raised great interest because of their high antitumor potency which, however, could not be transferred into highly efficient clinical regimens due to dose limiting side effects such as neutropenia. We have developed a new, highly potent pyrrole subclass of KSPis as a novel payload class in ADCs....

The DNA damage response (DDR) consists of complex signaling pathways that secure the integrity of the genome in eukaryotic cells. Numerous lines of evidence suggest that enhanced DNA damage caused by intrinsically or acquired defects in DDR, increases tumor immunogenicity, potentially impacting anti-tumor immune responses and sensitivity to immune...

p>Inhibitors of kinesin spindle protein (KSP/Eg5) have raised great interest because of their high antitumor potency which, however, could not be transferred into highly efficient clinical regimens due to dose limiting side effects such as neutropenia. We have developed a new, highly potent pyrrole subclass of KSPis as a novel payload class in ADCs...

Chemotherapy and immune checkpoint inhibitors (ICIs) are approved for treatment of non-small-cell lung cancer (NSCLC). However, there still remains a high medical need in NSCLC, eg. in patients non-responsive to ICIs or progressed after treatment with ICIs. Mesothelin (MSLN) is expressed in ~60% of lung adenocarcinomas. Here, we describe the mesoth...

Invited for the cover of this issue is the group of Hans‐Georg Lerchen and colleagues from Bayer AG R&D Pharmaceuticals. The image, provided by J. Franz and graphic designers from The New Atlantic (Cologne), depicts a cartoon representation of the legumain‐mediated cleavage of the peptide cap within the lysosome. Read the full text of the article a...

In the lysosome, legumain (LGMN in the picture) is required to release the active KSPi‐metabolite from antibody–prodrug conjugates, in addition to complete antibody degradation. High LGMN expression in solid tumors compared with healthy tissue may lead to drugs with further increased tumor selectivity and lower off‐target toxicity. More information...

Many antibody–drug conjugates (ADCs) have failed to achieve a sufficient therapeutic window in clinical studies either due to target‐mediated or off‐target toxicities. To achieve an additional safety level, a new class of antibody–prodrug conjugates (APDCs) directed against different targets in solid tumors is here described. The tumor‐associated l...

Gezieltes Abtöten von Tumorzellen mit Antikörper‐Wirkstoff‐Konjugaten (ADCs) unter Verwendung von Kinesin‐Spindelprotein(KSP)‐Inhibitoren als Ladung wird von H.‐G. Lerchen et al. in ihrer Zuschrift (DOI: 10.1002/ange.201807619) vorgestellt. Bei der Bindung des Antikörpers an tumorspezifische Antigene wird das ADC in lysosomale Kompartimente interna...

Targeted killing of tumor cells with antibody drug conjugates (ADCs) utilizing kinesin spindle protein inhibitor payloads is described in the Communication by H.‐G. Lerchen et al. (DOI: 10.1002/anie.201807619). Upon binding of the armed antibody to tumor specific antigens, the ADC is internalized into lysosomal compartments, where the active metabo...

The number of cytotoxic payload classes successfully employed in antibody‐drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) a...

The number of cytotoxic payload classes successfully employed in antibody‐drug conjugates (ADCs) is still rather limited. The identification of ADC payloads with a novel mode of action will increase therapeutic options and potentially increase the therapeutic window. Herein, we describe the utilization of kinesin spindle protein inhibitors (KSPi) a...

Despite remarkable results in treating certain cancers, immune checkpoint inhibitors (ICIs) are lack of activity in ‘cold' tumors and not always effective in inflamed ‘hot' tumors. In addition to aberrant activation in cancer cells, the PI3K pathway plays both positive and negative roles in immune response. Therefore, the overall outcome of PI3K in...

The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, only ADCs with microtubule inhibitors, DNA binding payloads or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC pay...

Antibody-drug conjugates (ADCs) are promising agents that are developed for targeted delivery of cytotoxic payloads to tumor cells. ADCs share a common design of antibody, linker, and cytotoxic payload. Despite significant efforts, the number of available payload classes with a differentiated mode-of-action that can successfully be employed to gene...

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA BAY-356 is a novel aglycosylated anti-TWEAK receptor antibody with potent agonistic activity evaluated for cancer therapy. In order to predict an efficacious therapeutic dose of BAY-356 in man, we sought to determine a therapeutic index where the exposure related to th...

TWEAK receptor (TWEAKR, FN14) is a member of the tumor necrosis factor receptor superfamiliy and is highly expressed in a variety of human solid tumor types, and its overexpression is associated with poor prognosis and metastasis. To explore targeting of TWEAKR for cancer therapy we have generated the novel, anti-TWEAKR antibody BAY-356. Its potent...

Purpose: Carbon-11- and fluorine-18-labeled choline derivatives are commonly used in prostate cancer imaging in the clinical setting for staging and re-staging of prostate cancer. Due to a limited detection rate of established positron emission tomography (PET) tracers, there is a clinical need for innovative tumor-specific PET compounds addressin...

The invention relates to novel antibody drug conjugates (ADCs), active metabolites of said ADCs, to methods for producing said ADCs, to the use of said ADCs for the treatment and/or prevention of diseases, and to the use of said ADCs for the prodn. of medicaments for the treatment and/or prevention of diseases, in particular hyperproliferative and...

Two new classes of radiolabeled GRP receptor antagonists are studied and compared with the well-established statine-based receptor antagonist DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2, 1; DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Sta:(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid)....