On November 12, 2021 Prelude Therapeutics Inc. (Nasdaq: PRLD), a clinical-stage precision oncology company, reported its financial results for the third quarter ended September 30, 2021 and provided an update on recent clinical and development pipeline progress (Press release, Prelude Therapeutics, NOV 12, 2021, View Source [SID1234595536]).

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"We continue to make significant progress advancing our novel pipeline of therapeutic candidates, most notably with the recent presentation of dose escalation data from the Phase 1 trials of our lead PRMT5 inhibitors, PRT543 and PRT811," said Kris Vaddi, PhD, Chief Executive Officer. "We were pleased by these initial data in unselected patients, which demonstrated key points of differentiation for our molecules, including good tolerability and potency, and a desirable therapeutic window. In addition, evidence of preliminary clinical activity was observed in multiple tumor types displaying preclinically validated genomic features. We look forward to leveraging learnings from these data as we execute on the dose escalation portion of the trials and evaluate PRT543 and PRT811 in biomarker-selected patient populations, with data readouts from these cohorts anticipated in 2022. Beyond our PRMT5 inhibitors, the balance of our pipeline continues to advance. During the quarter we received IND clearance from the FDA for PRT2527, our CDK9 inhibitor, positioning us to commence a Phase 1 study of this molecule before year-end."

Recent Highlights and Upcoming Milestones

PRT543

Phase 1 Dose Escalation Study Data Presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Annual Meeting; Data from Expansion Cohorts to be Presented in 2022: In October 2021, the Company presented data from the dose escalation portion of its Phase 1 trial of PRT543, which is designed to be a potent and selective inhibitor of PRMT5, in unselected patient populations. PRT543 demonstrated target engagement and inhibition of PRMT5 functional activity, as well as preliminary clinical activity. PRT543 was generally well tolerated. Patient enrollment is ongoing in specific biomarker-selected solid tumor and hematologic malignancy expansion cohorts. The Company expects to present data from the expansion cohorts in 2022.

Phase 1 Dose Escalation Data for PRT543 in Patients with Myeloid Malignancies to be Presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting: Data from the dose escalation portion of the ongoing Phase 1 clinical trial of PRT543 in patients with myelodysplastic syndrome (MDS) and myelofibrosis (MF), including safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity, will be featured during a poster session at the 63rd ASH (Free ASH Whitepaper) Annual Meeting and Exposition being held December 11-14, 2021.

PRT811

Phase 1 Dose Escalation Study Data Presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Annual Meeting; Dose Expansion Portion of Phase 1 Trial to Commence 4Q21: In October 2021, the Company presented data from the dose escalation portion of its Phase 1 trial of PRT811, which is designed to be a potent, selective, and brain penetrant PRMT5 inhibitor, in patients with unselected advanced solid tumors. PRT811 demonstrated dose dependent inhibition of PRMT5 activity and demonstrated signs of preliminary clinical activity. PRT811 was generally well-tolerated. Prelude will shortly commence the dose expansion portion of the Phase 1 trial in selected patients with central nervous system cancers (CNS) and non-CNS cancers. The Company expects to present data from the expansion cohorts in 2022.

PRT1419

Phase 1 Dose Escalation Portion of Oral and Intravenous (IV) PRT1419 Trial Ongoing: The dose escalation portion of the Company’s first-in-human Phase 1 study investigating both an oral and IV formulation of MCL-1 inhibitor, PRT1419, the Company’s third clinical candidate, in patients with relapsed/refractory hematologic malignancies, including acute myeloid leukemia and high-risk myelodysplastic syndromes, and solid tumors, remains ongoing. The Company expects to add dose expansion and combination cohorts to the Phase 1 clinical trial in the first half of 2022.

PRT2527

Dose Escalation Phase 1 Trial of PRT2527 on Track to Begin by Year-End: During the third quarter the Company received clearance for an Investigational New Drug (IND) application for PRT2527, which is designed to be a potent and selective CDK9 inhibitor. The Company anticipates beginning a Phase 1 trial of PRT2527 by year-end evaluating IV infusion monotherapy in patients with selected solid tumors.

Preclinical Data Presented at the AACR (Free AACR Whitepaper)-NCI-EORTC Annual Meeting: In October 2021, the Company presented new preclinical data demonstrating that intermittent intravenous administration of PRT2527 demonstrated strong efficacy in hematological malignancies and solid tumor models with MYC dysregulation.

Discovery Programs

The Company continues to expect to initiate IND-enabling studies for PRT-SCA2, which is designed to be a SMARCA2 protein degrader, by year-end. The Company also continues to make progress in the PRT-K4 discovery program and expects to initiate IND-enabling studies by year-end.

Corporate Update

On November 5, 2021, Brian Piper, our Chief Financial Officer, notified the Company that he will be resigning from the Company, effective November 19, 2021, to pursue other opportunities.

The Company reported the appointment of Laurent Chardonnet as its new Chief Financial Officer starting November 29, 2021. Mr. Chardonnet joins from Axcella Health where, since 2019, he served as Senior Vice President, CFO. Prior to Axcella, he spent 15 years at Incyte Corporation where he held roles of increasing responsibility including Vice President Finance, Treasurer and Principal Accounting Officer, Head of Finance and Administration for the company’s European division, and Vice President of Alliances and Global Strategy. Mr. Chardonnet received his Master of Business Administration from Vanderbilt University and his initial business degree from the Institut Supérieur de Gestion in Paris

The Company and Dr. David Mauro, the Company’s Chief Medical Officer, mutually agreed that Dr. Mauro would depart from the Company to pursue other opportunities. Dr. Mauro’s last day with the Company was on November 9, 2021. The Company has an ongoing search for a successor. Dr. Victor Sandor, former Chief Medical Officer of Array Biopharma and current board member and chair of the Science and Technology Committee, will provide strategic and operational oversight of clinical development during this time.

Third Quarter 2021 Financial Results

Cash, Cash Equivalents, and Marketable Securities: Cash, cash equivalents, and marketable securities as of September 30, 2021 were $320.9 million.

Research and Development (R&D) Expenses: For the third quarter of 2021, R&D expense increased by $7.4 million to $22.7 million for the three months ended September 30, 2021 from $15.3 million for the three months ended September 30, 2020. The increase was mainly due to increased clinical research costs to support the advancement of our clinical programs as well as an increase in discovery-stage program expenses. Our chemistry, manufacturing and other costs for the clinical trials also increased.

General and Administrative (G&A) Expenses: For the third quarter of 2021, G&A expense increased by $5.2 million to $8.1 million for the three months ended September 30, 2021 from $2.9 million for the three months ended September 30, 2020. The increase was primarily due to an increase in personnel related expense due to an increase in employee headcount and an increase in our professional fees as we expanded our operations to support our research and development efforts and incurred additional costs to operate as a public company.

Net Loss: For the third quarter of 2021, net loss was $30.7 million, or $0.66 per share, compared with a net loss of $16.8 million, or $5.25 per share, for the same period in 2020.

Financial Guidance: The Company believes that its current cash, cash equivalents and marketable securities will be sufficient to fund operating expenses and capital expenditure requirements into the second half of 2023.

On November 12, 2021 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported the company will be presenting posters with new data from three of its pipeline programs on Saturday, Nov. 13, at the 2021 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, being held virtually and in person in Washington, D.C. from Nov. 10-14 (Press release, Bolt Biotherapeutics, NOV 12, 2021, View Source [SID1234618693]). Each presentation highlights the progress made in preclinical studies to demonstrate the potential for each pipeline candidate as a novel approach for the treatment for cancer.

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"We are presenting new data for three of our pipeline programs that demonstrate the depth of our technology platform and the expertise of our team in modulating myeloid cell biology to develop promising therapeutic candidates," said David Dornan, Ph.D., Bolt Biotherapeutics’ Chief Scientific Officer. "Repolarizing tumor-associated macrophages, or TAMs, to become tumor destructive via the novel target Dectin-2 is groundbreaking work that may be synergistic with our entire Boltbody ISAC portfolio. Our work targeting CEA and PD-L1 reinforces our commitment to develop therapeutics that could have promising activity against solid tumors where limited treatment options are available."

Highlights of the three poster presentations follow, and copies of the posters are available on the Bolt Biotherapeutics website.
Poster #784: "BDC-2034: Discovery of a CEA-targeting Immune-Stimulating Antibody Conjugate (ISAC) for Solid Tumors"
Presenter: William G. Mallet, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
CEA is a well-validated tumor antigen for the development of targeted therapies addressing multiple types of solid tumors, such as colon cancer, where new treatment options are urgently needed. Given the abundance of innate immune cells in CEA-expressing cancers, innate immune stimulation presents a promising therapeutic strategy. Applying Boltbody platform technology, Bolt Biotherapeutics scientists have developed a novel CEA-targeted ISAC, BDC-2034, to exploit over-expression of CEA in cancers. BDC-2034 is designed to trigger the innate immune system, leading to adaptive anti-tumor immunity and tumor destruction.

BDC-2034 comprises a novel CEA-targeted, pro-phagocytic antibody conjugated to a proprietary TLR7/8 agonist payload. Both elements of this molecule are finetuned for selective immune activation in tumors.
New data reported at SITC (Free SITC Whitepaper) 2021 demonstrate both tumor cell clearance and innate immune activation in cellular and in vivo models of CEA-expressing cancers. Further, systemic administration in tumor-bearing animals results in tumor-selective immunity.
Based on these data, Bolt Biotherapeutics designated BDC-2034 as a clinical candidate and is currently conducting IND-enabling studies with the expectation to initiate BDC-2034 clinical development in 2022.
Poster #782: "PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models"
Presenter: Marcin Kowanetz, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
Bolt Biotherapeutics scientists are presenting for the first time preclinical data on a novel multifunctional PD-L1-targeted Boltbody ISAC that has demonstrated the potential to improve upon the efficacy of PD-L1/PD-1 inhibition, especially in tumor types that do not respond well to immune-checkpoint inhibition.

Bolt Biotherapeutics’ PD-L1 ISAC uniquely combines three mechanisms of action: the ADCP and myeloid cell activation of an ISAC, plus immune-checkpoint inhibition with the ability to act through PD-L1 expressed on both tumor and immune cells.
Data presented at SITC (Free SITC Whitepaper) 2021 demonstrate how PD-L1 ISAC induces robust, target-dependent activation of the immune system, including induction of immunological memory.
Treatment with PD-L1 ISACs led to an effective anti-tumor response that was substantially improved over PD-L1 antibody blockage in preclinical models.
Poster #862: "Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy"
Presenter: Justin A. Kenkel, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
For the first time, Bolt Biotherapeutics is presenting data providing preclinical validation of Dectin-2, formerly referred to as TAM1, as a novel target for cancer immunotherapy. Expressed by tumor-associated macrophages (TAMs), Dectin-2 is a pattern recognition receptor that stimulates proinflammatory cytokine production and antigen presentation to drive innate and adaptive immune responses.

Findings reported at SITC (Free SITC Whitepaper) 2021 demonstrate that agonism of Dectin-2 on TAMs elicits secretion of pro-inflammatory cytokines and chemokines capable of invoking productive anti-tumor immunity.
In murine tumor models, Dectin-2 agonism mediates anti-tumor efficacy in a CD8 T cell-dependent manner and induces immunological memory against the tumor.
Bolt Biotherapeutics scientists have generated Dectin-2 agonist antibodies that show the potential to reprogram tumor-supportive macrophages into tumor-destructive macrophages.
About the Boltbody Immune-Stimulating Antibody Conjugate (ISAC) Platform
ISACs are a new category of immunotherapy that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems. Boltbody ISACs comprise three primary components: a tumor-targeting antibody, a non-cleavable linker, and a proprietary immune stimulant to activate the patient’s innate immune system. By initially targeting a single marker on the surface of a patient’s tumor cells, an ISAC can create a new immune response by activating and recruiting myeloid cells. The activated myeloid cells start a feed-forward loop by releasing cytokines and chemokines, chemical signals that attract other immune cells and lower the activation threshold for an immune response. This reprograms the tumor microenvironment and invokes an adaptive immune response that targets the tumor, with the goal of durable responses for patients with cancer.

On November 12, 2021 Senti Bio, a leading gene circuit company, reported results from SENTI-401, one of its preclinical stage oncology programs, that aims to more precisely target tumors while sparing healthy cells (Press release, Senti Biosciences, NOV 12, 2021, View Source [SID1234596740]). The poster presentation, which is on display starting today at the Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), describes preclinical data from SENTI-401, a Logic Gated allogeneic, chimeric antigen receptor natural killer (CAR-NK) cell therapy development program for the treatment of colorectal cancer (CRC). The results support the Company’s vision of using gene circuits to create next-generation, "smart" cell and gene therapies with computer-like logic in human cells.

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Targeting of tumor-associated antigens, such as carcinoembryonic antigen (CEA), can result in severe clinical toxicities due to the killing of healthy epithelial cells whose cell surfaces also express CEA. This includes toxicity risk to cells in the colon and gastrointestinal tract as well as the lungs. SENTI-401 is designed to incorporate logic gating to target and kill CEA-expressing tumor cells, while preventing the killing of CEA-expressing healthy epithelial cells. The SENTI-401 NOT GATE pairs a CEA-targeting activating-CAR (aCAR) with an inhibitory-CAR (iCAR) that recognizes a safety antigen (SA) uniquely expressed in certain healthy gastrointestinal and lung epithelial cells. The SA was identified and validated through Senti Bio’s proprietary Bioinformatics-Driven Antigen Pairing (B-DAP) discovery platform. The poster highlights the SENTI-401 development program’s NOT GATE gene circuit technology as follows:

Killing of colorectal cancer cells:

Generated, tested and optimized anti-CEA CAR constructs for optimal performance in NK cells using Senti Bio’s Design-Build-Test-and-Learn (DBTL) platform.
Evaluated CAR-NK cells for anti-tumor activity, and demonstrated potent killing of CEA-expressing CRC target cells in vitro. A single dose of these CAR-NK cells also demonstrated anti-tumor activity in a human CRC xenograft model, reducing tumor burden in >33% of the treated mice.

Preservation of healthy cells:

iCAR suppressed aCAR mediated killing (p<0.05) in a SA-dependent manner without diminishing aCAR-mediated anti-tumor activity.
V-set and Immunoglobulin Domain Containing 2 (VSIG2), a membrane protein, was identified as the SA via Senti Bio’s B-DAP discovery platform and validated in healthy tissue samples. VSIG2 is uniquely expressed in CEA-positive healthy cells but not in tumor cells.
Used Senti Bio’s DBTL platform to evaluate multiple iCAR designs that utilize inhibitory domains that can selectively prevent CAR-mediated killing in an SA-dependent manner.

"Existing cancer therapies generally target only a single tumor-associated antigen, which means that they can only be used safely and effectively where that antigen is expressed primarily on tumor cells," said Alba Gonzalez, PhD, presenter of the abstract and Associate Director, Research at Senti Bio. "What is so exciting about our Logic Gating platform is the potential to advance a highly novel approach to CAR-NK based therapy that may more precisely treat colon cancer, and other solid tumors, with a reduced risk for on-target, off-tumor toxicities, thereby offering the potential to increase the therapeutic window and provide meaningful benefit to patients."

The abstract (Poster #116) is available on the SITC (Free SITC Whitepaper) website. The poster is available on the Senti Bio website.

About Logic Gating and NOT GATE Gene Circuits
Logic Gating gene circuits are designed to enable cell and gene therapies to control their therapeutic activity in response to the presence or absence of multiple disease biomarkers. NOT GATE gene circuits are one type of Logic Gates that are designed to widen the therapeutic window by enabling killing of cancer cells while preserving healthy cells. The NOT GATE functions by recognizing Safety Antigens on the cell surface, or antigens that are selectively expressed on healthy cells and not on cancer cells, thus limiting on-target, off-tumor killing. By protecting healthy cells, the NOT GATE has the potential to enable more effective on-target, on-tumor killing of tumor cells that express tumor-associated antigens.

On November 12, 2021 Alector, Inc. (Nasdaq: ALEC), a clinical-stage biotechnology company pioneering immuno-neurology, reported that preclinical data from its AL009 immuno-oncology program in poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 36th Annual Meeting (Press release, Alector, NOV 12, 2021, View Source [SID1234595375]).

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AL009 is a first-in-class fusion protein engineered to block multiple Siglecs. Siglecs (sialic acid binding immunoglobulin-like lectins) are a family of receptors involved in immune regulation that bind to cell surface sialic acid glycans. Siglecs are predominantly expressed on myeloid cells and the overexpression of Siglecs has been linked to immune suppression and evasion by tumor cells, as well as modulating the differentiation of myeloid cells into tumor-promoting macrophages. AL009 acts as a checkpoint inhibitor, blocking the immunosuppressive effect of multiple Siglecs and thereby enhancing both the innate and adaptive immune system response to cancer. Alector is developing AL009 for the potential treatment of solid tumor cancers and plans to initiate a first-in-human clinical trial of AL009 in 2022.

"Siglecs play a critical role in regulating immune activity, and our research into the role of the Siglec family of inhibitory receptors in neurodegenerative disease led to the discovery and optimization of AL009 for immuno-oncology. AL009 is a fusion protein uniquely able to block multiple Siglec receptors and halt Siglec-sialic acid-mediated immune suppression, which may be beneficial in a number of disease states where evasion of the immune system allows disease to progress unchecked," said Daniel Maslyar, M.D., Alector’s Vice President Clinical Development. "As we compared AL009 with other immunotherapies in preclinical models, we observe higher potency in blocking immune cell suppression and promising anti-cancer activity alone and in combination with anti-PDL1 in multiple tumor types, including some that have been found resistant to other immunotherapies. We look forward to advancing AL009 into the clinic to characterize its potential to treat a variety of solid tumor types."

In a poster titled "AL009, a Fusion Protein and Multi-Siglec Inhibitor, Repolarizes Suppressive Myeloid Cells and Potentiates Anticancer Effects," Alector researchers highlighted:

AL009 led to dose-dependent increases in immune stimulatory molecules consistent with the repolarization of myeloid-derived suppressive cells to a proinflammatory state
In vitro, AL009 increased T cell function by approximately 10 to 100-fold compared to other cancer immunotherapies
In syngeneic tumor models in mice that were less responsive to anti-PD-L1, treatment with AL009 showed efficacy in reducing tumor growth both as a single agent and in combination with anti-PD-L1
In a murine model of lung metastasis, AL009 combined with anti-TRP1 therapy to reduce lung nodules
The poster is available on Alector website in the Investors section at www.alector.com. Alector management will also be conducting a call for analysts and investors to discussion data presented this week for four of the company’s pipeline programs, AL001, AL101 and AL003 being developed for the treatment of neurodegenerative diseases and AL009.

About AL009
AL009 is a first-in-class multi Siglec inhibitor that works to enhance both the innate and adaptive immune system response to tumors by blocking a critical glycan checkpoint pathway that drives immune inhibition. Alector is initially developing AL009 for the potential treatment of solid tumors, with plans to initiate first-in-human clinical studies in 2022.

On November 12, 2021 Elicio Therapeutics, a clinical-stage biotechnology company developing a pipeline of novel immunotherapies for the treatment of cancer and other diseases, reported two ePoster presentations of preclinical data on its Amphiphile (AMP) platform in combination with TCR-T and CAR-T therapies, respectively, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting taking place in Washington D.C. and virtually November 10-14, 2021 (Press release, Elicio Therapeutics, NOV 12, 2021, https://elicio.com/2021/11/elicio-therapeutics-presents-preclinical-data-on-amp-tcr-t-and-car-t-combination-therapies-at-the-2021-society-for-immunotherapy-of-cancer-annual-meeting/ [SID1234595391]). The ePosters are available on the SITC (Free SITC Whitepaper) website starting November 12, 2021, at 7 a.m. ET., and accessible here.

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"These preclinical datasets demonstrate the broad potential of our AMP platform and build on previous data validating our AMP boosting approach to enhance already established TCR-T and CAR-T cell therapies. By successfully targeting the lymph nodes, AMP-boosting can enhance both adoptively transferred and endogenous T cell responses to activate potent, functional and durable immunity against tumors," said Peter DeMuth, Ph.D., Vice President of Research at Elicio Therapeutics. "We are excited to continue building on these data to enable clinical translation including through our collaboration with the Moffitt Cancer Center, where we are evaluating AMP-boosting of CD19 CAR-T therapies to promote durable CAR-T responses to tumors. With many patients failing to enter remission with CAR-T therapy alone or relapsing due to poor CAR-T persistence, this could be the boost that immunotherapy needs."

Data Presentation Details:

Title: Lymph Node Targeted Boosting with Cognate Amphiphile-Peptide Vaccines Enhances TCR-T Cell Therapy to Eradicate Solid Tumors

Abstract Number: 157

AMP boosting significantly enhanced TCR-T cell anti-tumor response and led to durable cures of solid tumors in an established, syngeneic tumor model.
AMP boosting delivers cognate peptides and adjuvant to lymph nodes, which induces dendritic cell (DC) activation and provides in vivo activation of tumor-specific TCR-T cells to amplify anti-tumor potency of adoptively transferred cells.
AMP-peptide pulsed autologous human DCs enhanced the function of clinically relevant human KRAS-specific TCR-T cells in vitro.
These studies provide direct rationale and evidence for the combination of AMP boosting with TCR-T cell therapies to augment clinical responses.
Title: Amphiphile-Peptide Boosting with FMC63-binding Surrogate Peptide Mimotopes Induces Activation and Potent Effector Function in CAR-T Cells Targeting CD19

Abstract Number: 552

The AMP platform can potentially be utilized as a mechanism to expand and functionally enhance CAR-T cells in vivo targeting blood and solid tumors.
AMP-peptides (AMPlifiers) effectively accumulate in lymph nodes and decorate lymph node resident antigen-presenting cells (APCs) as well as boost CAR-T activation and expansion in vivo.
Phage display screening enables AMPlifier discovery and validation for CAR scFv domains such as FMC63, the CD19 specific domain used in marketed CD19 CAR-T products.
In vitro, CD19 AMPlifiers induce phenotypic activation, cytotoxic and effector function in cognate CD19 CAR-T cells with 28z or BBz signaling domains.
About the Amphiphile Platform

Our proprietary Amphiphile, or AMP, platform delivers investigational immunotherapeutics directly to the "brain center" of the immune system – the lymph nodes. We believe this site-specific delivery of disease-specific antigens, adjuvants, and other immunomodulators may efficiently educate, activate, and amplify critical immune cells, potentially resulting in induction and persistence of potent adaptive immunity required to treat many diseases. In preclinical models, we have observed lymph-node specific engagement driving therapeutic immune responses of increased magnitude, function, and durability. We believe our AMP lymph node targeted approach will produce superior clinical benefits compared to immunotherapies that do not engage the lymph nodes.

Our AMP platform, originally developed at the Massachusetts Institute of Technology, or MIT, has broad potential across cancers, infectious diseases and other disease indications to advance a number of development initiatives through internal activities, in-licensing arrangements or development collaborations and partnerships.

The Amphiphile platform is thought to deliver immunotherapeutics directly to the lymph nodes by latching on to the protein albumin, found in the bloodstream, as it travels to lymphatic tissue. In preclinical models, we have observed lymph-node specific engagement driving therapeutic immune responses of increased magnitude, function, and durability.