Antibodies For Treatment Of Cancer Research Articles

Progress of lymphocyte activation gene 3 and programmed cell death protein 1 antibodies for cancer treatment: A review.

The application of immune checkpoint inhibitors has proven to be an effective treatment for cancer. Immune checkpoints such as programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T-cell immunoglobulin-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene-3 (LAG-3) have received extensive attention, and the efficacy of antibodies or inhibitors against these checkpoints (either alone or in combination) has been evaluated in many tumors. This paper provides a brief overview of the PD-1 and LAG-3 checkpoints, and then shifts focus to the combined use of PD-1 and LAG-3 antibodies in both in vivo and in vitro experiments. In the in vitro experiments, we examined the correlation between the expression and activation of these inhibitors on T cells, and also assessed toxicity in animals in preparation for in vivo experiments. The effects of the combined use of PD-1 and LAG-3 antibodies were then summarized in animal models of melanoma, MC38 carcinoma, and other tumors. In clinical studies, the combined application of these antibodies was assessed in patients with melanoma, colorectal, breast, and renal cell cancers, as well as other solid tumors. In general, the combination of PD-1 and LAG-3 antibodies has shown promising results in both in vivo and in vitro studies.

Anti-PD-1 antibodies recognizing the membrane-proximal region are agonists that can stimulate immunosuppressive activity of PD-1

Abstract The success of immunoenhancing anti-PD-1 blocking antibodies in cancer treatment indicates the biological significance of PD-1-dependent immunoregulation in the human immune system. Active stimulation of PD-1 is potentially an effective approach in treating various inflammatory disorders; however, agonistic anti-PD-1 antibodies stimulating the immunosuppressive activity are not clearly defined. Here, by assessing the biological activities of anti-human PD-1 mAbs, we have identified functional anti-PD-1 agonists in the antibody group recognizing the membrane-proximal extracellular region (MPER). MPER recognition was characteristic to anti-PD-1 agonist mAbs and distinct from blocking mAbs binding to the membrane-distal region of PD-1. The agonistic activity was mediated by Fc receptor-dependent co-ligation of PD-1 molecules. In vivo anti-inflammatory efficacy of the PD-1 agonist in murine disease models suggests its clinical potential to various inflammatory disorders including autoimmune diseases. Meiji Seika Pharma, Co., Ltd. Foundation for Biomedical Research and Innovation at Kobe

The Clinical Application of Bispecific Antibodies in Cancer Treatment

Bispecific antibody (bsAb) is a type of human-modified antibody which two or more sites are capable of binding two or more individual antigens. This dual specificity enables bsAbs to have superior application than the monoclonal antibodies as they can eliminate tumour cells via recruiting T cells and also the accessory immune cells in some cases, as well as can simultaneously block two different signalling pathways or different disease mediator. More than 30 technologies have been applied for the development of bsAbs based on heavy chains and light chains heterologous recombination. However, only three bsAbs have been approved and available on the market, whereas over 110 BsAbs are at different clinical or research stages. In this paper, different types of bsAbs will be elaborated as well as the clinical significance of the approved bsAbs.

Therapeutic Antibodies in Cancer Treatment in the UK

The growing understanding of the molecular mechanisms of carcinogenesis accelerated the development of monoclonal therapeutic antibodies to specifically target multiple cancer pathways. Recombinant protein therapeutics now constitute a large proportion of yearly approved medicines. Oncology, autoimmune diseases and to a smaller degree the prophylaxis of organ transplant rejection are their main application areas. As of the date of this review, 37 monoclonal antibody products are approved for use in cancer treatments in the United Kingdom. Currently, the antibody therapeutics market is dominated by monoclonal immunoglobulins (IgGs). New types of recombinant antibody therapeutics developed more recently include bispecific recombinant antibodies and other recombinantly produced functional proteins. This review focuses on the approved therapeutic antibodies used in cancer treatment in the UK today and describes their antigen targets and molecular mechanisms involved. We provide convenient links to the relevant databases and other relevant resources for all antigens and antibodies mentioned. This review provides a comprehensive summary of the different monoclonal antibodies that are currently in clinical use primarily in malignancy, including their function, which is of importance to those in the medical field and allied specialties.

Expression of plant-produced anti-PD-L1 antibody with anoikis sensitizing activity in human lung cancer cells via., suppression on epithelial-mesenchymal transition.

Immune checkpoint antibodies in cancer treatment are receptor-ligand pairs that modulate cancer immunity. PD-1/PD-L1 pathway has emerged as one of the major targets in cancer immunotherapy. Atezolizumab, the first anti-PD-L1 antibody approved for the treatment of metastatic urothelial, non-small cell lung, small cell lung and triple-negative breast cancers, is produced in Chinese Hamster Ovary (CHO) cells with several limitations i.e., high-production costs, low-capacity yields, and contamination risks. Due to the rapid scalability and low production costs, the transient expression in Nicotiana benthamiana leaves was investigated by co-infiltration of Agrobacterium tumefaciens GV3101 cultures harboring the nucleic acid sequences encoding for Atezolizumab heavy chain and light chain in this study. The transient expression of Atezolizumab in transformed N. benthamiana accumulated up to 86.76 μg/g fresh leaf weight after 6 days of agroinfiltration (OD 600 nm: 0.4) with 1:1 ratio of heavy chain to light chain. The structural and functional characteristics of plant-produced Atezolizumab was compared with commercially available Tecentriq® from CHO cells with similar binding efficacies to PD-L1 receptor. The direct anti-cancer effect of plant-produced anti-PD-L1 was further performed in human lung metastatic cancer cells H460 cultured under detachment condition, demonstrating the activity of anti-PD-L1-antibody on sensitizing anoikis as well as the suppression on anti-apoptosis proteins (Bcl-2 and Mcl-1) and modulation of epithelial to mesenchymal regulating proteins (E-cadherin, N-cadherin, Snail and Slug). In conclusion, this study manifests plants as an alternative cost-effective platform for the production of functional monoclonal antibodies for use in cancer therapy.

Development of a human phage display-derived anti-PD-1 scFv antibody: an attractive tool for immune checkpoint therapy

BackgroundThe PD-1 checkpoint pathway plays a major role in tumor immune evasion and the development of the tumor microenvironment. Clinical studies show that therapeutic antibodies blocking the PD-1 pathway can restore anti-tumor or anti-virus immune responses by the reinvigoration of exhausted T cells. Because of the promising results of anti-PD-1 monoclonal antibodies in cancer treatment, autoimmune disorders, and infectious diseases, the PD-1 has emerged as an encouraging target for different diseases.ResultsIn the present study, we employed a human semi-synthetic phage library for isolation of some scFvs against the extracellular domain of PD-1 protein by panning process. After the panning, a novel anti-PD-1 scFv (SS107) was found that exhibited specific binding to PD-1 antigen and stimulated Jurkat T cells. The selected anti-PD-1 scFv could restore the production of IL-2 and IFN-γ by Jurkat T cells that were co-cultured with PD-L1 positive tumor cells.ConclusionThis anti-PD-1 scFv with high specificity and the ability to reactivate exhausted T cells has the potential to be developed as an anti-cancer agent or to be used in combination with other therapeutic approaches.

Abstract 1734: Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform

Abstract Background: Though antibodies for cancer treatment have achieved clinical and commercial success over the past few decades, a large portion are limited by suboptimal efficacy and on-target off-tumor toxicity due to ubiquitous expression of their targets. A plethora of molecular engineering approaches have been introduced to restrict the activity of antibodies solely to tumor instead of healthy tissue with the goal of improving the therapeutic index, such as masking the binding sites of antibodies with inhibitory domains. However, sophisticated modification is usually required while the outcomes are often mediocre. Previously we developed an ultra-pH sensitive nanoparticle platform named ON-BOARD. The strength of this technology stems from its ability to preferentially release the payload specifically in the acidic tumor microenvironment while staying intact in normal tissue. The safety and feasibility of using such a platform have been demonstrated by successful delivery of fluorophore to tumors for imaging of multiple tumor types in Phase I and II clinical trials with Pegsitacianine (formerly “ONM-100”). Pegsitacianine has been shown to be generally well-tolerated with an infusion-related reaction as the most common adverse event in the clinical trials conducted to date. Based on the clinical results, we present the ON-BOARD platform herein as a potential universal and effective tool for tumor specific activation and delivery of therapeutic antibodies without the need for sophisticated antibody chemistry or engineering. Methods: Biosimilar monoclonal antibodies of atezolizumab, cetuximab, pembrolizumab, trastuzumab, and ipilimumab with the same variable region sequences as the original pharmaceutical drugs were used to demonstrate encapsulation by the ON-BOARD platform and pH-dependent activation. Encapsulated antibodies were purified using SEC and the encapsulation efficiencies were quantified by HPLC. Particle size and uniformity were studied by DLS. The formulations were accessed for bioactivity in vitro under neutral pH or acidified conditions using appropriate cell-based reporter assays. Results: ON-BOARD nanoparticles successfully encapsulated the antibodies mentioned above without additional modification of the original antibody. Encapsulation efficiency ranged from 50-100%. The formulations were characterized as uniformly distributed particles < 100nm in size with good stability. In vitro assessment by cell-based reporter assays demonstrated > 100-fold activation window between the acid-activated and intact formulations. The pH-dependent activation was further confirmed by affinity and binding assay. Conclusions: The ON-BOARD pH-sensitive nanoparticle platform demonstrated potential as an effective and universal tool for tumor specific activation and delivery of antibody-based therapeutics. Citation Format: Gaurav Bharadwaj, Qingtai Su, Stephen Gutowski, Curran Parpia, Ashley Campbell, Jason Miller, Tian Zhao. Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1734.

Abstract 1644: Generation and validation of humanized GARP mice for testing novel anti-human GARP antibodies

Abstract GARP is a type I transmembrane protein expressed on regulatory T cells (Tregs) and platelets. GARP expression has been shown to play an important role in the modulation of latent TGF-β1 activity by regulatory T lymphocytes (Tregs), and thus, GARP has emerged as an important regulator of peripheral immune tolerance. While GARP expression is critical for homeostasis, increased GARP expression on Tregs is associated with elevated immunosuppression in the context of tumor biology. Because of these immunomodulatory roles, targeting GARP in the context of oncologic or other diseases is of significant interest. Thus, the development of mouse models for safety and efficacy evaluation of GARP-targeted therapeutics prior to clinical trials is needed. To facilitate assessment of novel anti-human GARP antibodies, Biocytogen has generated a humanized GARP mouse model for in vitro functional validation and in vivo efficacy evaluation assays. Using CRISPR-based gene editing technology, the exons of the mouse Garp gene that encode the extracellular domain were replaced by the human GARP counterpart. mRNA Expression of the human GARP extracellular domain was confirmed in splenocytes isolated from homozygous humanized mice. Expression of human GARP was readily detected in FoxP3+ Treg cells isolated from the spleen of humanized GARP mice as assessed by flow cytometry. Importantly, the frequency of FoxP3+ Tregs and other mature leukocyte subpopulations, including T and B lymphocytes, Natural killer cells, dendritic cells, granulocytes, and monocytes/macrophages, was also similar in the blood and spleen of humanized GARP mice compared to wild-type mice. Subsequent in vivo efficacy assays using the MC38 tumor model demonstrated efficacy of the anti-human GARP antibody in slowing tumor growth in humanized GARP mice. Furthermore, combination of anti-human GARP and anti-mouse PD-1/PD-L1 blockade resulted in a significantly greater tumor inhibition than monotherapies. In summary, GARP humanized mice are a powerful platform for preclinical evaluation of anti-human GARP antibodies for cancer treatment. Citation Format: Ruili Lyu, Huilin Li, Jenna Frame, Yuelei Shen. Generation and validation of humanized GARP mice for testing novel anti-human GARP antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1644.

Abstract LB534: Development of GB2101, a novel anti-CCR8 antibody for cancer treatment

Abstract Background: Regulatory T cells (Tregs) play a crucial role in suppressing immune response and maintaining hemostasis and immune tolerance. Tregs are enriched in the tumor microenvironment (TME) and suppress anti-tumor immunity. Therefore, specific depletion of Tregs in the TME is expected to reduce anti-tumor immune suppression without affecting hemostasis in the periphery. The C-C motif chemokine receptor 8 (CCR8), highly expressed on Tregs from TME but significantly lower expressed on Tregs from peripheral blood, provides an ideal target for preferentially deletion of Tregs within tumors. GB2101 is a novel anti-CCR8 monoclonal antibody generated from hybridoma. The data from in vitro and in vivo studies indicated that GB2101 is a good PCC molecule with great potential for clinical development. Methods: GB2101 was generated by immunization of CCR8 gene plus CCR8 over-expressing cells in mice followed by hybridoma technology. The binding of the antibody to CCR8-expressing cells was detected by flow cytometry. CCL1 ligand blocking was assessed by flow cytometry and calcium flux assay. Antibody-dependent cell-mediated cytotoxicity (ADCC) function was evaluated by Jurkat-CD16A-NFAT reporter system. In vivo anti-tumor efficacy was assessed in syngeneic model using human CCR8 knock-in mice. Results: GB2101 displayed potent binding to cells expressing CCR8. GB2101 efficiently blocked CCL1 binding and CCL1-induced signals in CCR8 expressing cells. ADCC activity against target cells was observed and afucosylated version of GB2101 improved ADCC response. GB2101 significantly inhibited tumor growth in syngeneic model. Conclusions: GB2101 is a novel monoclonal antibody specifically binding to CCR8 with high affinity, and efficiently blocked CCL1-CCR8 pathway and suppressed tumor growth in vivo. Therefore, it is a very promising preclinical candidate that may be used in the treatment of multiple tumor types. Citation Format: Qinglin Du, Yiqi Cao, Xueyan Yang, Jing Lu, Fei Peng, Wenming Zhou, Liwen Liang, James Li, Shuhua Han. Development of GB2101, a novel anti-CCR8 antibody for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB534.

Bringing Together the Power of T Cell Receptor Mimic and Bispecific Antibodies for Cancer Immunotherapy: Still a Long Way to Go.

Antibody-based cancer immunotherapy has revolutionized oncology. The first successful therapeutic antibodies relied on eliciting immune-mediated cytotoxicity (rituximab) or modulation of intracellular signaling (trastuzumab). Further attempts to enhance the antitumor effects led to the development of immunoconjugates with radioactive or cytotoxic compounds (tositumomab, brentuximab vedotin). Another line of research led to the bispecific antibodies that can enhance the formation of immunological synapse between cancer and cytotoxic T cells (blinatumomab). Despite the constant advances in design and production, the application of monoclonal antibodies in cancer treatment remains limited by the presence of specific cell surface markers. A rational approach to target intracellular cancer antigens was proposed almost two decades ago by the development of anti-peptide human leukocyte antigen (HLA) complex (T cell receptor-like/mimic) antibodies. They could recognize specifically cancer neoantigens expressed in the context of specific HLA molecules theoretically providing unprecedented specificity. Furthermore, they can be developed in a semigeneric format, that is, to target common neoantigens expressed in the context of common HLA molecules. It is rationale to expect that the development of such antibodies in the format of bispecific antibody constructs can bring together the power of specific antibody-based recognition and that of T cell-mediated lysis. There are already some preliminary reports that suggest such constructs would be an achievable goal. In this brief review, we discuss some of the successful preclinical developments in the field and the major challenges that are yet to be addressed.

Agonistic CD40 Antibodies in Cancer Treatment.

Simple SummaryCD40 is a costimulatory molecule that is key for the activation of antigen-presenting cells and other innate immune cells. It plays an important role in anti-tumor immunity, and agonists of CD40 have been shown to eliminate tumors in both pre-clinical and clinical settings, alone and in combination with other treatment modalities. Here we assess the expression of CD40 and associations with other mediators of immunity in a variety of tumor types and review the potential of CD40 agonists for cancer treatment, given the promise of enhancing the interplay between innate and adaptive immunity.CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

Discovery of the RANKL/RANK/OPG system.

Almost a quarter century has passed since discovery of receptor activator of NF-κB ligand (RANKL). This discovery had a major impact on identification of mechanisms regulating osteoclast differentiation and function, establishment of a research field bridging bone and the immune system (osteoimmunology), and development of a fully human anti-RANKL neutralizing antibody (denosumab). Denosumab is now clinically available for treatment of osteoporosis and cancer-induced bone diseases in the US, Europe and many other countries, including Japan. Denosumab is a so-called blockbuster drug, with sales of 5.0 billion US dollars in 2019. This is a real success story from bench to bedside. In this review, the pivotal roles of the RANKL/RANK/OPG system in osteoclast differentiation and function are shown. RANKL is a ligand required for osteoclast generation, RANK is the receptor for RANKL, and osteoprotegerin (OPG) is a decoy receptor for RANKL. The review covers recent results showing the importance of RANKL on osteoblasts in regulation of osteogenesis and the role of RANKL-RANK dual signaling in coupling of bone resorption and formation, including demonstration of RANKL reverse signaling that we had previously hypothesized. Possible applications of anti-RANKL antibody in treatment of cancer are also discussed.

Evaluation of the Efficiency of Protein A Affinity Chromatography to Purify a Monoclonal Antibody for Cancer Treatment and its Purity Analysis

Background: Protein A affinity chromatography is often employed as the most crucial purification step for monoclonal antibodies to achieve high yield with purity and throughput requirements. Introduction: Protein A, also known as Staphylococcal protein A (SPA) is found in the cell wall of the bacteria staphylococcus aureus. It is one of the first discovered immunoglobulin binding molecules and has been extensively studied since the past few decades. The efficiency of Protein A affinity chromatography to purify a recombinant monoclonal antibody in a cell culture sample has been evaluated, which removes 99.0% of feed stream impurities. Materials and Method: We have systematically evaluated the purification performance by using a battery of analytical methods SDS-PAGE (non-reduced and reduced sample), Cation Exchange Chromatography (CEX), Size-exclusion chromatography (SEC), and Reversed phased-Reduced Chromatography for a CHO-derived monoclonal antibody. Results and Discussion: The analytical test was conducted to determine the impurity parameter, Host Cell Contaminating Proteins (HCP). It was evaluated to be 0.015ng/ml after the purification step; while initially, it was found to be 24.431ng/ml. Conclusion: The tests showed a distinct decrease in the level of different impurities after the chromatography step. It can be concluded that Protein A chromatography is an efficient step in the purification of monoclonal antibodies.

Current Development of Monoclonal Antibodies in Cancer Therapy.

Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.

DIY: Visualizing the immune landscape of tumors using transcriptome and methylome data.

The importance of the immune system in combating many different types of malignancies has been firmly established. Indeed, the success of immune checkpoint-blocking antibodies in cancer treatment has focused the attention of many researchers on the tumor immune microenvironment. As one consequence, the analysis of the number, type, and activation status of tumor-infiltrating leukocytes (TILs) has become an area of great interest. Detailed knowledge of the immunological profile of a given tumor has the potential to predict patient response to therapy and overall survival. This chapter is intended to summarize the steps necessary for basic comparative analysis of the infiltration and activation status of immune cells in various human solid tumors, using freely available data obtained from The Cancer Genome Atlas (TCGA).

Abstract 2400: K01401-020 is a novel anti-VISTA antibody for cancer treatment: Pharmacodynamic impact on non-human primates and human immune system

Abstract VISTA (V-domain Ig suppressor of T cell activation), also known as PD-1 homolog (PD-1H), is a transmembrane protein which is highly expressed in myeloid cells such as neutrophils, monocytes, macrophages, and dendritic cells, and at low levels on naive CD4, CD8 and regulatory T-cells. VISTA is also expressed in cancer cells in some patient subsets (Villarroel-Espindola, 2017; Böger, 2017; Liao, 2018). VISTA is functionally described as a negative checkpoint regulator of immune response. Hence, VISTA blockade increases proliferation when T cells are stimulated with VISTA expressing myeloid antigen presenting cells (Wang et al, 2011). Immune suppression by VISTA-positive cells has been hypothesized in the primary or acquired resistance to cancer immunotherapy (Kakhavand, 2017); and even a negative impact of VISTA on immune response has been functionally demonstrated in prostate cancer samples from patients having received prior immunotherapy (Gao, 2017). Here we show that VISTA RNA and protein are expressed in lung cancer samples. We also show by using bioinformatics, that VISTA expression is linked to the higher myeloid infiltrated tumors and can also be found in tumor cells. K01401-020 is novel monoclonal, humanized IgG antibody that binds to cynomolgus monkey and human-VISTA (hVISTA) with a high affinity (Kd ~0.1 nM). The antibody binds to VISTA extracellular domain and blocks its associated function. The pharmacology of K01401-020 was studied in a series of in vitro (ex vivo) experiments with human blood cells, and in vivo studies in non-human primates. Peripheral Blood Mononuclear cells (PBMCs) from several couples of human donors were mixed together in a Mixed Lymphocyte Reaction (MLR) setting, which showed that K01401-020 stimulated IFNg release after 5 days of culture. K01401-020 stimulates NK cells to proliferate and induces activating cytokines by NK cells and monocytes, contributing to T cell activation. PDL1 expression is also clearly induced on myeloid cells by K01401-020, suggesting that combination therapy with anti-PD1/L1 may be required to optimize the anti-tumor efficacy. In non-human primates, preliminary results show that both K01401-020 monotherapy, given weekly at 3 dose levels for 4 weeks and anti-VISTA antibody combination with anti-PD1 antibody (pembrolizumab) were well tolerated. Pharmacodynamic exploration using peripheric blood sampling demonstrated full VISTA occupation by the antibody, and notably, dendritic cell activation. K01401-020 antibody drug is thus expected to increase global and specific anti-tumor immune response in situations where VISTA is expressed in cancer patients and may be synergistic with anti-PD1/L1 antibodies. Citation Format: Noureddine Loukili, Isabelle Vandenberghe, Olivier Delfour, Françoise Fraboul, Eric Chetaille, Francisco Cruzalegui, Nathalie Corvaïa, Pierre J. Ferré. K01401-020 is a novel anti-VISTA antibody for cancer treatment: Pharmacodynamic impact on non-human primates and human immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2400.

Daratumumab-225Actinium conjugate demonstrates greatly enhanced antitumor activity against experimental multiple myeloma tumors

ABSTRACT Daratumumab is an anti-CD38 directed monoclonal antibody approved for the treatment of multiple myeloma (MM) and functions primarily via Fc-mediated effector mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, and T-cell activation. However, not all patients respond to daratumumab therapy and management of MM remains challenging. Radioimmunotherapy with alpha particle-emitting radionuclides represents a promising approach to significantly enhance the potency of therapeutic antibodies in cancer treatment. Here we report the results of mechanistic and feasibility studies using daratumumab radiolabeled with an alpha-emitter 225Actinium for therapy of MM. CD38-positivelymphoma Daudi cell line and MM cell lines KMS-28BM and KMS-28PE were treated in vitro with 225Ac-daratumumab. 225Ac-daratumumab Fc-functional properties were assessed with C1q binding and ADCC assays. The pharmacokinetics and tumor uptake of 111In-daratumumab in Daudi tumor-bearing severe combined immunodeficiency (SCID) mice were measured with microSPECT/CT. The therapeutic effects of 225Ac-daratumumab on Daudi and KSM28BM tumors in mice and treatment side effects were evaluated for 50 days posttreatment. The safety of 225Ac-labeled antimurine CD38 mAb in immunocompetent mice was also evaluated. 225Ac-daratumumab efficiently and specifically killed CD38-positive tumor cells in vitro, while its complement binding and ADCC functions remained unaltered. MicroSPECT/CT imaging demonstrated fast clearance of the radiolabeled daratumumab from the circulation and tissues, but prolonged retention in the tumor up to 10 days. Therapy and safety experiments with 225Ac-daratumumab showed a significant increase in the antitumor potency in comparison to naked antibody without any significant side effects. Our results highlight the potential of targeting alpha-emitters to tumors as a therapeutic approach and suggest that 225Ac-daratumumab may be a promising therapeutic strategy for the treatment of hematologic malignancies.

Pros and Cons of the Immunogenicity of Monoclonal Antibodies in Cancer Treatment: A Lesson from Autoimmune Diseases

The aim of this review is to report the current evidence on immunogenicity of monoclonal antibodies (moAbs)used in cancer compared with autoimmune diseases, focusing on local microenvironment. English abstracts were identified in Medline and www.clinicaltrials.gov . A total of 82 papers were selected. The percentage of immunogenicity of moAbs used for cancer therapy, evaluated as the serum concentration of antidrug antibodies, is significantly lower than that of moAbs used for the treatment of autoimmune diseases. This condition may rely on a different immunologic background characterized by a hyperactivation of immune cells in autoimmune diseases. The formation of complexes between antidrug antibodies and non-neutralizing moAbs bound to neoplastic antigens may allow more efficient elimination of cancer cells, but additional studies are needed.

Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity.

The immune checkpoint molecules are emerged in the evolution to protect the host from self-attacks by activated T cells. However, cancer cells, as a strategy to survive and expand, can hijack these molecules and mechanisms to suppress T cell-mediated immune responses. Therefore, an idea of blocking the checkpoint molecules to enhance the anti-tumor activities of the host immune system has been developed and applied to the cancer therapy after discovery of the inhibitory T cell co-receptor, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and further enhanced on the identification of PD-1 and its ligands. Since 2010, several checkpoint inhibitors have been approved by FDA and many more are in clinical trials. In the treatment of advanced cancers, these inhibitors significantly increased response rates and survival benefits. However, accompanied with the striking results, immune-related adverse events (irAEs) that broadly occurred in many organs were observed and reported, some of which were fatal. Herein, we first review the recent progressions in the research of the immune checkpoint molecules and the application of their blocking antibodies in cancer treatment, and then discuss the cardiac toxicity induced by the therapy and the strategy to monitor, manage this adverse event when it occurs.

Screening of Monoclonal Antibodies for Cancer Treatment

With the rapid development of cancer treatment using monoclonal antibodies (mAbs), the screening process of suitable biologics and indications attracts much attention. A general definition of ‘screening’ in the biopharmaceutical industry includes three aspects: the appropriate biologics for the specific cancers, the appropriate indications for the specific biologics and the promising biologic candidates from the pool at the pre-clinical drug discovery stage. Effective screening strategies in the biopharmaceutical industry are crucial to accelerate the drug commercialization process and select the effective biologics for patients. The current status of commercial mAbs and the global pharmaceutical market was briefly reviewed. The mechanism of commercial mAbs and the indications, as well as the current technologies for mAbs screening in the new drug discovery and cell line development stages were systematically reviewed, with an aim as a beneficial reference for screening highquality mAbs, appropriate indications with efficient technologies.