bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1831: Affinity tuned XmAb®2+1 GPC3 x CD3 bispecific antibodies demonstrate selective activity in liver cancer models
Authors: Nisthal Alex , Hassanzadeh-Kiabi Nargess , Avery Kendra N. , Rashid Rumana , Diaz Juan E. , Muchhal Umesh S. , Chu Seung Y. , Moore Gregory L. , Bykova Katrina , Desjarlais John R. 
Published: July 2021

Abstract
Bispecific T cell engagers simultaneously bind CD3 on T cells and tumor-associated antigens to promote T cell-mediated killing of tumor cells. These agents provide synthetic immunity by expanding, activating, and redirecting T cells against a target of interest. While targeting lineage-restricted antigens such as CD19 or CD20 have found clinical success in hematopoietic cancers, targeting solid tumors requires high expressing tumor associated antigens (TAAs) with minimal normal tissue expression.
Glypican 3 (GPC3), a lipid-anchored cell surface protein, is over-expressed in the majority of hepatocellular carcinoma (HCC) and a smaller subset of lung squamous cell carcinoma. It is considered an ideal target because its expression is not detected in adult tissues, and its function can promote tumor growth through the Wnt/beta-catenin pathway. Although GPC3 demonstrates good differential expression, bispecific T cell engagers are powerful immunomodulatory agents and careful tuning can improve the therapeutic window on all targets.
Building upon the XmAb® heterodimeric Fc platform, we generated bispecific antibodies in an XmAb 2+1 Fab2-scFv-Fc format that are bivalent for GPC3 and monovalent for CD3. Reducing the affinity of GPC3 encouraged avid binding and strong killing activity only on high GPC3 expressing cell lines while minimizing reactivity on low expressing cell lines. We found modulating the CD3 affinity, either directly through mutation or indirectly by the molecular format, contributes to the selectivity of the bispecific antibodies. To ensure biologically valid antigen densities were being considered, IHC was conducted on paraffin embedded arrays of tumor tissue, normal tissue, and cell lines. Upon matching the staining intensity between the three sample types, we identified cell lines with corresponding GPC3 antigen density that could serve as proxies of tumor and normal tissue. In vitro T cell-dependent cellular cytotoxicity (TDCC) assays on the relevant cell lines confirmed selective potency on high versus low expressing cells.
Citation Format: Alex Nisthal, Nargess Hassanzadeh-Kiabi, Kendra N. Avery, Rumana Rashid, Juan E. Diaz, Umesh S. Muchhal, Seung Y. Chu, Gregory L. Moore, Katrina Bykova, John R. Desjarlais. Affinity tuned XmAb®2+1 GPC3 x CD3 bispecific antibodies demonstrate selective activity in liver cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1831.
Abstract 1832: Development of a splicing modulator-based ADC payload class with immune stimulatory properties for cancer therapy
Authors: Mitra Satyajit K. , Jammalamadaka Vasu , Kang Jeffrey , Losic Teodora , Tuffy Greg , Liang Tony W. , Tipton Kim , Lopez Adriana , Savage Scott , Monteith William , Haskins William E. , Jurica Melissa S. , Satyal Sanjeev , Do Mary 
Published: July 2021

Abstract
Background: Thailanstatins are naturally occurring anti-proliferative compounds that target spliceosomes and modulate pre-mRNA splicing. Alterations in splicing machinery and mRNA splicing is common in cancer and represents a potential susceptibility that can be exploited by targeted delivery of a splicing modulator to tumors with antibody drug conjugates (ADCs).
Results: PH1 payload is a novel derivative of Thailanstatin optimized for metabolic stability and anti-tumor activity. PH1 is an efficient modulator of splicing in vitro and in vivo and a poor substrate for the MDR1 transporter. Transcriptome analysis of PH1- treated NCI-N87 cells revealed multiple classes of mis-splicing events including elevated expression of transcripts with skipped exons (3364 genes/4x change) and retained introns (332 genes/2.5x change). Translation of transcripts with retained introns and novel exon-exon junctions results in generation of neoepitopes.
Upon conjugation to Trastuzumab, Tras PH1 ADC exhibited nanomolar potency specific to HER2-expressing cancer cells, with durable anti-tumor response in vivo and favorable pharmacokinetic exposure in mice. Due to the potential for generation of neoepitopes, combination studies of Tras PH1 with a checkpoint inhibitor antibody was performed in a syngeneic MC38-HuHer2 model. Single agent and combination treatments induced tumor recruitment of CD11b+ positive myeloid cell subsets. While the combination treatment eradicated tumors, the treated animals also developed tumor-specific immunity.
A toxicology study performed in cynomolgus monkeys confirmed favorable PK profile and a wide safety margin for Tras PH1 ADC.
Conclusions: We present the development of a splicing modulator-based payload class with the ability to target tumor mRNA splicing, induce tumor neoepitopes, recruit myeloid cells and generate anti-tumor immunity. These findings support the development of ADCs using this novel class of immunostimulatory payload.
Citation Format: Satyajit K. Mitra, Vasu Jammalamadaka, Jeffrey Kang, Teodora Losic, Greg Tuffy, Tony W. Liang, Kim Tipton, Adriana Lopez, Scott Savage, William Monteith, William E. Haskins, Melissa S. Jurica, Sanjeev Satyal, Mary Do. Development of a splicing modulator-based ADC payload class with immune stimulatory properties for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1832.
Abstract 1843: Dicovery and characterization of a novel anti-human CXCR5 antibody for the treatment of B cell lymphomas
Authors: Kok Ayrin , Margallducos Germain , Beq Stephanie , Monchecourt Clarisse , Poullain Hombline , David Muriel , George Carine , Ellouze Sami , Chen Mingjie , Lu Yun-Yueh , Li Juying , Zhang Qian , Wang Jean , Adrian Francisco , Schweizer Liang , Beltraminelli Nicola 
Published: July 2021

Abstract
CXCR5 is a seven transmembrane protein coupled to protein G(i) expressed mainly on mature, resting B cells, follicular helper T cells (TFH), tonsillar B cells, and B cell lymphoma cells. CXCR5 is activated by its ligand CXCL13 and involved in cell migration. Dysregulated CXCL13 and/or CXCR5 expression and signaling have been associated with cancer promotion, as well as autoimmune and chronic inflammatory disorders. Overexpression of CXCL13 in autoimmune and lymphoproliferative disorders has been shown to correlate with disease progression. We therefore hypothesized that an antibody that selectively depletes CXCR5+ malignant B cells through antibody dependent cell-mediated cytotoxicity (ADCC) could be developed to treat B cell lymphomas. Here, we present preclinical data supporting the rationale for indication selection, biomarker identification, dose selection, and phase I clinical trial design. Using our single-cell screening platform technology, CelliGo™, we identified a panel of monoclonal antibodies against human CXCR5. We selected HFB2-4, which binds to CXCR5 expressing cells, blocks CXCL13-induced intracellular signaling and B cell migration, and induces ADCC of Raji B cell lymphoma cells at sub-nM concentrations. HFB2-4 demonstrates good PK behavior in mice and exhibits potent anti-tumor activity in a Raji xenograft murine model. HFB2-4 efficacy in this model is comparable to that of rituximab, despite a lower number of huCXCR5 receptors compared to CD20 on the surface of Raji cells. Our data shows that HFB2-4 holds promise as a therapeutic agent for B cell lymphoproliferative diseases by depleting CXCR5+ tumor B cells in refractory B cell lymphoma and lymphomas derived from severe Sjogren syndrome. Compared to the emerging treatments for refractory B cell lymphomas such as Antibody-Drug-Conjugates, bi-specific antibodies or cell therapies, HFB2-4 may represent a well-tolerated, efficacious, cost-efficient and easy to manufacture alternative.
Citation Format: Ayrin Kok, Germain Margallducos, Stephanie Beq, Clarisse Monchecourt, Hombline Poullain, Muriel David, Carine George, Sami Ellouze, Mingjie Chen, Yun-Yueh Lu, Juying Li, Qian Zhang, Jean Wang, Francisco Adrian, Liang Schweizer, Nicola Beltraminelli. Dicovery and characterization of a novel anti-human CXCR5 antibody for the treatment of B cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1843.
Abstract 1845: Enhancing the efficacy of antitumor antibodies with immune checkpoint inhibitors and targeted therapy in melanoma
Authors: Pérez-Lorenzo Rolando , Erjavec Stephanie O. , Clynes Raphael , Christiano Angela M. 
Published: July 2021

Abstract
The therapeutic outcomes of current strategies in melanoma treatment have greatly improved within the last decade. However, the persistent relatively low success rate of current standard-of-care strategies underscores the urgent need for improvement of these therapeutic approaches. The use of specific antitumor antibodies recently transformed the cancer therapeutics landscape with successes such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, antitumor antibodies have not been developed for the treatment of melanoma. Here, using mouse preclinical models of melanoma (both solid tumor and lung metastasis), we found that the therapeutic efficacy of the specific antitumor antibody TA99 (anti-TYRP1) is significantly enhanced by immune checkpoint blockade. This was associated with a greater CD8+, CD8+/Foxp3+, NK1.1+ and dendritic cell infiltrate, suggestive of an increased anti-tumor immune response. Further, MEK inhibition (MEKi) increased the expression of melanosomal antigens in B16 and YUMM mouse melanoma cell lines in vitro. We next combined TA99 and MEKi to treat B16 melanoma in vivo and observed a synergistic reduction in tumor growth. Treatment of mice bearing YUMM melanoma (BRAF mutant) with TA99/MEKi resulted in the complete elimination of tumors in the majority of animals, and produced durable responses. Moreover, we found a synergistic effect when B16 tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which, in combination with antitumor antibodies, generated a robust adaptive antitumor response that was sustained by immune checkpoint inhibition therapy. These improved therapeutic effects of specific antitumor antibodies by current standard-of-care therapeutics have potential near-term translation to the clinic, in light of fully humanized anti-TYRP1 antibodies currently in clinical development.
Citation Format: Rolando Pérez-Lorenzo, Stephanie O. Erjavec, Raphael Clynes, Angela M. Christiano. Enhancing the efficacy of antitumor antibodies with immune checkpoint inhibitors and targeted therapy in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1845.
Abstract 1852: A novel PD1-CD40 bispecific antibody YH008 induces potent anti-tumor activity in vivo by PD1 dependent activation of CD40 signaling
Authors: Liu Baihong , Hui Li , Liu Chonghui , Li Zhihong , Pan Fangxia , Yang Benny , Lin Qingcong 
Published: July 2021

Abstract
Immunotherapies that target PD1/PDL1 pathway have marked a new era of cancer therapy. Combinatorial treatment of inhibiting PD1/PDL1 signaling and other immunomodulating agents has been widely tested and validated as a better strategy compared to single agent treatment. CD40 (TNFRSF5) is a member of the TNFR super family, a key T cell co-stimulatory signal critical for B-cell maturation and immunoglobulin class switching. Biocytogen developed a novel first in class PD1-CD40 bispecific antibody (YH008) that agonizes CD40 conditionally upon PD1 binding. In vitro study data shows YH008 can block the interaction of PD1 to PDL1 and induced dose dependent NFAT activation. YH008 was able to activate human CD40 on reporter cells in the presence of PD1-expressing jurkat cells in a dose dependent manner without relying on FcγR expressing cells. This feature is beneficial for conditionally activation of CD40+ cells in tumor microenvironment and tumor-draining lymph nodes, where tumor specific PD1+ T cells are enriched. In vivo study result shows that YH008 demonstrated robust anti-tumor efficacy against MC38 and B16F10 tumors in PD1/CD40 double humanized mice (B-hPD1/hCD40). In hCD40 mice which has no human PD1 engagement, YH008 did not show anti-tumor activity against MC38 tumor. Furthermore, YH008 did not elevate liver enzymes of MC38 bearingB-hPD1/hCD40 mice at dose as high as 26 mg/kg, demonstrating improved liver safety profile than selicrelumab. Taken together, these data demonstrated that YH008 is a promising new immunotherapeutic candidate in cancer treatment.
Citation Format: Baihong Liu, Li Hui, Chonghui Liu, Zhihong Li, Fangxia Pan, Benny Yang, Qingcong Lin. A novel PD1-CD40 bispecific antibody YH008 induces potent anti-tumor activity in vivo by PD1 dependent activation of CD40 signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1852.
Abstract 1865: Simultaneous de-repression of innate and adaptive immune responses through dual targeting of ILT4 and PD(L)-1 with bispecific antibodies
Authors: Vitale Laura , Murphy Mike , Weidlick Jeff , Wasiuk Anna , O'Neill Thomas , Widger Jenifer , Mills-Chen Laura , Crocker Andrea , Patterson Colleen , Boyer James , Crew Linda , Natoli Edward J. , Lillquist Jay S. , Goldstein Joel , Thomas Lawrence J. , Marsh Henry C. , Alvarado Diego , Keler Tibor 
Published: July 2021

Abstract
Activation of innate immunity using targeted therapies has become an attractive approach to stimulate antitumor responses. Dual inhibition of receptors that suppress myeloid and T cell compartments through the generation of bispecific antibodies (bsAbs) is a promising strategy to overcome resistance to checkpoint inhibition. Activation of the ITIM-bearing ILT4/LILRB2 receptor by its cognate ligands (HLA-G and HLA Class I) in myeloid cells induces a strong immunosuppressive response that may be leveraged by tumors to evade immune surveillance. Monoclonal antibodies (mAbs) that inhibit ILT4 activity have demonstrated promising preclinical and early clinical data in combination with PD-1 inhibitors, including in the checkpoint refractory setting. These findings provide a rationale to co-target ILT4 with PD(L)-1 using a single molecule. We describe the discovery and characterization of ILT4 inhibitory mAbs for engineering bsAbs that revert myeloid cell suppression by antagonizing ILT4 and activate T cell responses through PD(L)-1 inhibition. Humanized anti-ILT4 mAbs were generated that specifically bind human and macaque ILT4. These mAbs exhibit sub-nanomolar HLA-G binding to ILT4 expressing cells. Macrophages treated with ILT4 mAbs release inflammatory cytokines/chemokines and upregulate activation markers resulting in polarization to an M1 inflammatory phenotype. These activities are further potentiated in the presence of toll-like receptor activation with lipopolysaccharide (LPS). We engineered tetravalent bsAbs using an Fc-silenced IgG1 linked to scFv format from our anti-ILT4 and anti-PD-L1 mAbs in both orientations. The bsAbs have good biophysical characteristics and retain functional properties similar to the parental mAbs. Further in vitro and in vivo characterization efforts are ongoing to select the bsAb candidate to enter development activities and IND-enabling studies.
Citation Format: Laura Vitale, Mike Murphy, Jeff Weidlick, Anna Wasiuk, Thomas O'Neill, Jenifer Widger, Laura Mills-Chen, Andrea Crocker, Colleen Patterson, James Boyer, Linda Crew, Edward J. Natoli, Jay S. Lillquist, Joel Goldstein, Lawrence J. Thomas, Henry C. Marsh, Diego Alvarado, Tibor Keler. Simultaneous de-repression of innate and adaptive immune responses through dual targeting of ILT4 and PD(L)-1 with bispecific antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1865.
Abstract 1870: Novel conditionally active bispecific T cell engagers targeting solid tumors
Authors: Liu Haizhen , Wang Jing , Cugnetti Ana Paula G. , Xing Charles , Wheeler Christina , Lucas Matthew , Chang Cathy , Frey Gerhard , Boyle William , Short Jay 
Published: July 2021

Abstract
The use of CD3/target bispecific molecules has great therapeutic potential in oncology. This potential, however, is diminished due to severe cytokine release effects as well as serious on-target off-tumor toxicities. Conditionally Active Biologic (CAB) technology is a proprietary platform that generates bispecific antibodies which have no or very little binding to CD3 and to the tumor target antigen (TAA) in healthy tissue (normal physiological conditions), but have strong binding in the context of diseased tissues (tumor microenvironment) based on the glycolytic tumor metabolism (including Warburg effect). Using our CAB technology, we have developed dual-CAB (CAB TAA x CAB CD3) bispecific antibodies targeting two well-established tumor associated antigens, B7H3 and Nectin4. These dual-CAB bispecific antibodies were developed so that they bind to recombinant CD3 and TAA as well as to CD3 and TAA expressing cells under in vitro tumor microenvironment conditions, but not in physiologic conditions. In vitro characterization and in vivo efficacy data of the dual-CAB TAA x CD3 bispecific antibodies targeting B7H3 and Nectin4 will be presented. The CAB technology allows the generation of a new class of potent T-cell engagers with increased safety margin and therapeutic index in the clinic.
Citation Format: Haizhen Liu, Jing Wang, Ana Paula G. Cugnetti, Charles Xing, Christina Wheeler, Matthew Lucas, Cathy Chang, Gerhard Frey, William Boyle, Jay Short. Novel conditionally active bispecific T cell engagers targeting solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1870.
Abstract 1874: MDX-124, a novel annexin-A1 antibody, induces an anti-tumor immune response and wide-ranging anti-cancer activity in multiple preclinical models
Authors: Dempsey Fiona C. , Al-Ali Hussein , Crichton Scott J. , Pepper Chris , Parris Christopher N. 
Published: July 2021

Abstract
Major recent advances have increased the understanding of both the molecular mechanisms and the immune response in cancer. This has led to the discovery of new agents that regulate the tumor immune microenvironment. Annexin-A1 (ANXA1) is a phospholipid binding protein that has been shown to have immunomodulatory effects on T-cells, macrophages and dendritic cells. Although normally localized in the cytoplasm, ANXA1 is secreted in response to a number of different stimuli and can modulate cellular functions through interactions with formyl peptide receptors (FPR1/2). Overexpression of ANXA1 has been observed in several cancer types including triple-negative breast (TNBC), lung, pancreatic and ovarian, and correlates with poor prognosis and decreased overall survival. Furthermore, ANXA1 has also been shown to influence cancer cell proliferation, angiogenesis, migration and drug resistance. Hence, we explored the role of MDX-124, a novel humanized antibody targeting ANXA1, and here present data from several pre-clinical cancer models.
Results: Incubation of a panel of cell lines representing several histological cancer subtypes with MDX-124 for 72h resulted in a statistically significant dose-dependent reduction in cell viability compared to control. ANXA1 expression in the subcellular compartments (nucleus, cytoplasm and membrane) was quantified in a panel of cancer cell lines via imaging flow cytometry and the anti-proliferative effect of MDX-124 was shown to correlate with membrane ANXA1 expression. Using a transwell assay, TNBC and acute myeloid leukemia cell lines exposed to MDX-124 exhibited a statistically significant reduction in migration compared to untreated controls. We also observed that MDX-124 induced antibody dependent cellular cytotoxicity (ADCC) activity in a dose-dependent manner using a reporter bioassay (EC50 = 0.38 nM). MDX-124 was further evaluated in an additional panel of in-vitro assays and shown to exert consistent anti-cancer activity.
In conclusion, our data indicate that targeting ANXA1 with MDX-124 inhibits tumorigenic processes and induces an immune response in tumors overexpressing ANXA1. MDX-124 therefore provides an innovative approach to cancer therapy. Investigations are continuing to explore the efficacy of MDX-124 in syngeneic mouse models as both a single agent and in combination with standard of care agents.
Citation Format: Fiona C. Dempsey, Hussein Al-Ali, Scott J. Crichton, Chris Pepper, Christopher N. Parris. MDX-124, a novel annexin-A1 antibody, induces an anti-tumor immune response and wide-ranging anti-cancer activity in multiple preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1874.