Michael Briskin - Academia.edu (original) (raw)

Papers by Michael Briskin

Journal of Experimental Medicine, Nov 22, 2004

Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progr... more Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433-1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.

Proceedings of the National Academy of Sciences of the United States of America, Mar 1, 1991

Heritable retroviral transgenes are highly expressed in chickens (transgenic chickens/defective r... more Heritable retroviral transgenes are highly expressed in chickens (transgenic chickens/defective retroviral vector/gene expression)

Journal of Immunology, Apr 15, 1996

Organization, regulatory sequences, and alternatively spliced transcripts of the mucosal addressi... more Organization, regulatory sequences, and alternatively spliced transcripts of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) gene.

The Journal of Immunology

The mucosal vascular addressin, MAdCAM-1, is an Ig family adhesion receptor preferentially expres... more The mucosal vascular addressin, MAdCAM-1, is an Ig family adhesion receptor preferentially expressed by venular endothelial cells at sites of lymphocyte extravasation in mucosal lymphoid tissues and lamina propria. MAdCAM-1 binds the lymphocyte homing receptor for Peyer's patches, the integrin alpha 4 beta 7. We describe a point mutation within the first Ig domain of MAdCAM-1 that abolishes activation-independent alpha 4 beta 7 binding. This point mutation resides within an eight-amino acid motif with homology to sequences important for the integrin binding ability of the related vascular Ig family members, ICAM-1 and VCAM-1. To understand the contributions of the individual MAdCAM-1 domains, chimeric exchanges with the beta 1 integrin ligand, ICAM-1, were made. The two N-terminal domains of MAdCAM-1 are sufficient to confer alpha 4 beta 7 binding comparable to that of native MAdCAM-1. A chimera containing only the N-terminal Ig domain (domain 1) of MAdCAM-1 can also bind (to a ...

Journal of Leukocyte Biology

We have examined the expression of homing receptors on circulating memory B cells subsets. Blood ... more We have examined the expression of homing receptors on circulating memory B cells subsets. Blood IgD+ (naive) B cells homogeneously express a high level of intestinal homing receptor, α4β7, but IgD− (putative memory) B cells comprise distinct α4β7+ and α4β7− subsets. Naive and α4β7+ memory B cells but not α4β7− cells bind MAdCAM-1, suggesting that α4β7 expression may predict B cell intestinal homing. In contrast, α4β7+ and α4β7− B cells bind well to VCAM-1, possibly allowing recruitment of both subsets to extra-intestinal sites, including those tissues of the “common mucosal immune system” characterized by vascular VCAM-1 expression. sIgA+ B cells, which are associated with mucosal immunity in the gut and elsewhere, are heterogeneous in homing receptor expression—with discrete subsets expressing α4β7, L-selectin, and cutaneous lymphocyte antigen (CLA). sIgA+ CLA+ B cells are enriched by binding to E-selectin, suggesting that CLA may participate in B cell homing to nonintestinal muco...

Cancer Research

Background: While checkpoint inhibitors (CPIs) such as anti-CTLA-4 and anti-PD-1/L1 have demonstr... more Background: While checkpoint inhibitors (CPIs) such as anti-CTLA-4 and anti-PD-1/L1 have demonstrated efficacy in a number of solid tumor indications, those with high stromal presence have been difficult to treat with minimal response observed. We aimed to use a proprietary machine learning/artificial intelligence platform to identify novel stromal targets to relieve this immunosuppressive barrier and increase CPI responsiveness in difficult to treat indications. Methods: Based on bioinformatic analysis using our single cell RNA atlas, we assessed cancer-associated fibroblasts (CAFs)/fibroblastic cells in cancer tissue for identification of novel targets, including proteoglycans. Antibodies were generated by immunization of humanized mice, and lead antibodies were tested for activity in inhibiting cell adhesion and were further characterized for staining of both CAFs as well as tumor cells. ADCs were developed and tested in vitro for selective tumor cell killing. Results: Bioinforma...

Blood, 1997

The tendency for gastric mucosa-associated lymphoid tissue (MALT) lymphoma cells preferentially t... more The tendency for gastric mucosa-associated lymphoid tissue (MALT) lymphoma cells preferentially to localize around reactive B-cell follicles, both in the mucosa and regional lymph nodes, coupled with their immunophenotype, has led to the proposal that the normal cell counterpart of this lymphoma is the marginal zone B cell. In keeping with this proposition, lymphocytes expressing the lymphoma idiotype have been detected in the splenic marginal zone in a single case of gastric MALT lymphoma. To confirm that this truly represented preferential homing of MALT lymphoma to the splenic marginal zone, we have now re-examined this case, together with 17 other cases, using both immunohistochemical and molecular methods in an attempt to establish clonal identity between the gastric lymphoma and cells in the splenic marginal zone. In three cases, the spleen was characterized by marked expansion of marginal zones by cells showing the same pattern of Ig light chain restriction as the gastric lym...

Cancer Chemistry, 2019

Since the first small molecule proteolysis targeting chimera (PROTAC) was reported about a decade... more Since the first small molecule proteolysis targeting chimera (PROTAC) was reported about a decade ago, great progress has been made in the field of targeted protein degradation. Specially designed, small molecules can recruit the ubiquitin-proteasome system (UPS) to tag a protein of interest (POI) for degradation. Based on the ability to knock down a therapeutic POI (instead of inhibiting the target protein activity), this new modality has emerged as a paradigm-shifting approach and opened new avenues for small molecule drug discovery. At Xios Therapeutics, we have applied targeted protein degradation to a number of immuno-oncology (IO) drug targets and we present here the strategy and lessons learned from building our PROTAC platform in collaboration with X-Chem. Specifically, we have leveraged a vertical integration of DNA-encoded library screening (DEL), structural biology, medicinal chemistry, biochemical binding assays and cellular biomarker readouts for the rapid identification of cell potent degraders. We exemplify a modular, ‘fit-for-purpose’ PROTAC matrix that allows for rapid exploration of optimal E3 ligase-binders conjugated to a POI-binder using either existing or novel ligands identified via DEL. We delineate the structure-activity/property relationship (SAR and SPR) analysis of linker with VHL- and CRBN-based binders for a promising IO target achieving potent protein degradation (>90% degradation and nM DC50 potency) and pathway inhibition in cancer cells. Notably, our affinity-based screening of chemical libraries of unprecedented size (~200 billion molecules) with a priori knowledge of the vector point of attachment from the DNA barcode directly informs the rational design of bifunctional PROTAC molecules. In conclusion, our integrated approach allows us to find new, unexplored compound binding sites for both E3 ligases- and POI-binders that can be utilized by the PROTAC platform to create potent selective degraders and to access targets that have previously been considered undruggable. Citation Format: Jannik N. Andersen, Andrew J. McRiner, Lynette A. Fouser, Junyi Zhang, Shilpi Arora, Michael Cordeau, Ying Zhang, John Cuozzo, Michael Briskin, Matt Clark, Diala Ezzeddine. Degradation of immuno-oncology targets via proprietary PROTAC platform integrating DNA-encoded library technology and rational drug design [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 981.

Cancer Research, 2016

The goal of this collaboration was to enable early quantitative thought experiments and risk asse... more The goal of this collaboration was to enable early quantitative thought experiments and risk assessments by developing and interrogating a quantitative systems pharmacology (QSP) model of the co-modulation inhibitory receptors PD-1 and TIM-3 in immuno-oncology. The QSP model was to: (1) provide predictions of best-in-class profiles for a PD-1 and TIM-3 fixed dose combination (FDC) and dual antagonist platforms, and (2) provide biological insights. The QSP model was based on first principles as a system of elementary mass-action, mechanistic PKPD, ordinary differential equations. The model parameters and reactions were based on biophysics, and are interpretable. The model reactions include protein synthesis and elimination, ligand-receptor and drug-target formation and turnover, and drug administration and first order clearance. There were four versions of the model: PD-1 monospecific, TIM-3 monospecific, PD-1 x TIM-3 bispecific and fixed dose combination (FDC) targeting PD-1 and TIM...

The American journal of pathology, 1997

In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case... more In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case of primary gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) with a secondary intestinal spread. We compared the findings with that observed in B cells of normal MALT and MALT acquired as a consequence of Helicobacter pylori-associated gastritis and other low-grade gastric B-cell MALT lymphomas. The neoplastic B cells in the gastric tumor were alpha 4 beta 7-, CD62L+, whereas the intestinal secondary was alpha 4 beta 7+, CD62L-. Incubation of isolated tumor cells from the stomach by H. pylori generated T-cell-dependent proliferation of neoplastic B cells and induced expression of alpha 4 beta 7 integrin similar to the intestinal tumor. These observations indicate that reversal of homing receptor profile in the gastric tumor by antigen specific stimulation may be responsible for secondary intestinal dissemination. In normal stomach and normal MALT, alpha 4 beta 7 and CD...

Advances in Immunology, 1999

... Press Inc. Published by Elsevier Inc. Permissions &amp;amp;amp;amp; Reprints. Lymphoc... more ... Press Inc. Published by Elsevier Inc. Permissions &amp;amp;amp;amp; Reprints. Lymphocyte Trafficking and Regional Immunity. Eugene C. Butcher ... in the periphery (1-14). Like all leukocytes, lymphocytes develop with characteristic trafficking properties. ...

Proceedings of the National Academy of Sciences, 1988

The enhancer element of the human immunodeficiency virus type I (HIV-I) long terminal repeat (LTR... more The enhancer element of the human immunodeficiency virus type I (HIV-I) long terminal repeat (LTR) contains two copies of nearly identical sequences AGGGACTTTCC (3G sequence) and GGGGACTTTCC (4G sequence) that are important in transcriptional regulation. A single copy of the 4G sequence is found in the NF-kappa B site of the immunoglobulin kappa-chain enhancer. Only the 4G motif in the HIV enhancer is bound by cellular proteins in extracts prepared from unstimulated HeLa cells, whereas the 3G and 4G motifs are bound by factors in extracts prepared from HeLa cells treated with phorbol esters [phorbol 12-myristate 13-acetate (PMA)] and lymphoid cells. To determine if this change in binding to the HIV enhancer was due to phosphorylation of a cellular protein, partially purified PMA-treated HeLa nuclear extracts were digested with calf intestinal phosphatase. Phosphatase digestion of nuclear extracts from PMA-treated HeLa cells markedly decreased factor binding to the HIV enhancer. Acco...

Nature, 1993

Tissue-specific homing of lymphocytes is regulated by interactions with the endothelium of specia... more Tissue-specific homing of lymphocytes is regulated by interactions with the endothelium of specialized venules, such as the high endothelial venules (HEV) in lymph nodes and mucosal lymphoid tissues. The mucosal vascular addressin, a 58-66K glycoprotein adhesion receptor for lymphocytes, is selectively expressed on HEV of mucosal lymphoid organ and on lamina propria venules and helps direct lymphocyte traffic to these mucosal tissues. We now report the isolation of a complementary DNA that, on transfection into COS cells, encodes immunoreactive addressin that specifically binds the mucosal HEV-binding T-cell lymphoma TK1. The predicted amino-acid sequence defines the mucosal addressin as a novel immunoglobulin family member, MAdCAM-1, with two amino-terminal domains that display strong homology to previously described vascular adhesion receptors for leukocytes, ICAM-1 (ref. 6) and VCAM-1 (ref. 7). The membrane proximal domain is homologous to the third domain (C alpha 2) of another mucosa-associated immunoglobulin family member, IgA1 (refs 8, 9). In addition to the immunoglobulin domains, there is a serine/threonine-rich region which may serve as a backbone to present carbohydrate ligands to lymphocytes. MAdCAM-1 is thus a complex multidomain receptor displaying several structural motifs that may participate in lymphocyte homing interactions.

Journal of Hepatology, 2003

Inflammatory Bowel Diseases, 1997

hibitors correlated with impaired actin function in endothelium. These findings show that leukocy... more hibitors correlated with impaired actin function in endothelium. These findings show that leukocyte passage across endothelial monolayers is more complex than previously appreciated and involves multiple steps that encompass structural alterations in lateral junctional glycoproteins and/or proteasomedependent signalling cascade. These findings point to novel endothelial-dependent mechanisms for regulation of neutrophil transmigration across activated endothelium. REFERENCES Read MA, Neish AS, Luscinskas FW, Palombella VJ, Maniatis T, Collins T. The proteasome pathway is required for cytokineinduced endothelial leukocyte adhesion molecule expression.

Gastroenterology, 2001

Background & Aims: In adults, binding of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) to... more Background & Aims: In adults, binding of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) to lymphocyte ␣4␤7 integrin directs cell trafficking to gut, whereas interaction of peripheral node addressins (PNAd) with lymphocyte L-selectin targets immune cells to peripheral lymph nodes (PLNs). Because nothing is known about these addressins during human development, we studied the expression and function of MAdCAM-1 (and PNAd for comparison) in fetuses and children. Methods: Series of human tissue samples obtained from fetuses (7-40 weeks), children (2 months-7 years), and adults were immunostained with monoclonal antibodies. The function of the addressins and their lymphocyte counter-receptors was tested in in vitro binding assays on fetal and adult tissues. Results: Unlike in adults, MAdCAM-1 is widely expressed from embryonic week 7 onwards, and it only gradually becomes polarized to mucosal vessels after birth. In utero MAdCAM-1 functionally governs lymphocyte adhesion to vessels both in the gut and PLNs by binding to ␣4␤7 integrin. The later induction of PNAd gradually starts to dominate the binding of lymphocytes to PLNs during childhood. Conclusions: There are striking age-dependent switches and species-specific variation in the molecular mechanisms of lymphocyte migration. In utero and during early childhood, the mucosal addressin MAdCAM-1 plays a dominant role in lymphocyte-endothelial cell adhesion at mucosal and nonmucosal sites.

Gastroenterology, 1996

Background & Aims: Integrins play diverse roles in celpresenting cells, and may direct and regula... more Background & Aims: Integrins play diverse roles in celpresenting cells, and may direct and regulate cellular lular actions and signaling in the immune system. In migration within tissues, cellular differentiation, and rethe context of mucosal immune responses, the integrin sponses to inflammatory stimuli through interactions a4b7 has received particular attention because of its with these adhesion proteins and extracellular matrix intimate involvement in lymphocyte recruitment to norcomponents such as fibronectin. 3,7,8 These diverse cellular mal gastrointestinal mucosa and associated lymphoid adhesion events likely contribute to both normal and tissue. The aim of this study was to determine the pathological mucosal immune and inflammatory refunctional relevance of a4b7 in the pathogenesis of sponses. colonic inflammatory disease using the colitic cotton-Captive cotton-top tamarins (CTTs; Saguinus oedipus), top tamarin, an animal model of human ulcerative colia New World nonhuman primate species, develop spontis. Methods: Chronically colitic cotton-top tamarins taneous and often chronic colitis that clinically and histowere given either a cross-reactive monoclonal antibody logically resembles ulcerative colitis in humans. 9 Because to human a4b7 or an irrelevant control monoclonal antibody. The animals were then evaluated clinically of the selective expression of a4b7 to memory lymphoand mucosal biopsy specimens assessed by histologicytes presumed to be specialized for mucosal immune cal and quantitative morphometric analysis. Results: A responses, we reasoned that a4b7 might represent a poblocking monoclonal antibody to a4b7 integrin ameliotent and selective target for the therapeutic modulation rated inflammatory activity and rapidly improved stool of lymphocyte-mediated mucosal inflammation of the consistency when administered to chronically colitic colon. In this study, we report that a monoclonal antianimals. Furthermore, using morphometric analysis of body to a4b7 integrin rapidly resolves diarrhea and cobiopsy specimens, antibody therapy reduced the mucolonic inflammatory activity when administered to chronisal density of a4b7 / lymphocytes and a4b7 0 neutrocally colitic CTTs. Furthermore, the relative density of phils and macrophages. Conclusions: These results mucosal leukocyte subsets is greatly attenuated in resuggest that the a4b7 integrin represents a novel, posponse to immunotherapy with an antibody to a4b7. tentially organ-specific therapeutic target for the treatment of inflammatory bowel disease.

European Journal of Immunology, 1996

T cells show a bias in their migration pathways: some T cells preferentially migrate to periphera... more T cells show a bias in their migration pathways: some T cells preferentially migrate to peripheral lymph nodes (LN), some to mucosal tissues, and some to peripheral tissues such as skin. These recirculation pathways were examined in sheep by collecting lymph draining into and out of peripheral and intestinal LN, and using fluorescent dyes to trace the recirculation of the lymph cells. Monoclonal antibodies (mAb) to α4, β1, and β7 integrins, and L‐selectin, were used to define three major populations of recirculating T cells. Naive‐type T cells (L‐selectin+, α4β1lo β7lo) migrated preferentially through peripheral LN. Two memory populations could be defined: α4β1hi β7− and α4β7hiβ1lo. α4β1hi β7− T cells were present in lymph draining from the skin. T cells migrating preferentially through intestinal LN were α4β7hi β1lo. Consistent with this migration pattern, the endothelial receptor for α4β7, mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) was detected on high endothelial venul...