Last update 01 Jul 2024

Lorukafusp alfa

Last update 01 Jul 2024

Overview

R&D Status

Clinical Result

Translational Medicine

Overview

Basic Info

Drug Type

Fusion protein

Synonyms

Anti-ganglioside-GD2-antibody-interleukin-2-fusion-protein, APN 301, APN-301

+ [6]

Target

GD2 x IL-2R

Mechanism

GD2 inhibitors(Disialoganglioside GD2 inhibitors), IL-2R agonists(Interleukin-2 receptor agonists)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesOther Diseases+ [2]

Active Indication

MelanomaNeuroblastomaRetinoblastoma

Inactive Indication

GD2 Positive GliomaMelanoma, Cutaneous MalignantNeuroblastoma recurrent+ [3]

Originator Organization

Lexigen Pharmaceuticals Corp.

Active Organization

APEIRON Biologics AGLexigen Pharmaceuticals Corp.

Merck Sharp & Dohme Corp.

Inactive Organization

National Cancer Institute

EMD Serono, Inc.

Bristol Myers Squibb Co.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

Gene Sequence

Sequence Code 45370L

Source: *****

Sequence Code 616720214H

Source: *****

Clinical Trials associated with Lorukafusp alfa

NCT03958383 / SuspendedPhase 1/2IIT

Phase I/II Intratumoral Administration of Hu14.18-IL2, With Local Radiation, Nivolumab and Ipilimumab in Subjects With Advanced Melanoma

This phase I/II trial is designed to determine the maximum tolerated dose or the maximum administered dose of intratumoral administration of hu14.18-IL2 and to evaluate side effects of intratumoral hu14.18-IL2 when given alone, after radiation therapy, after radiation therapy and in combination with nivolumab, and after radiation therapy and in combination with nivolumab and ipilimumab in patients with melanoma that is advanced (stage IV) or with melanoma that cannot be removed by surgery and is considered surgically incurable. Hu14.18-IL2 is a molecule called a fusion protein that can bind to some tumor cells and cause immune cells to become activated to kill tumor cells. Radiation therapy is a type of cancer treatment that uses beams of high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with immune checkpoint inhibitors, such as nivolumab and ipilimumab, can help the body's immune system attack cancer by releasing the "brakes" on the immune system to allow cancer fighting immune cells to remain activated. This study will evaluate whether giving intratumoral hu14.18-IL2 with radiation therapy, nivolumab and ipilimumab has antitumor activity for participants with advanced melanoma.
After completion of study treatment, participants are followed up at 30 days, every 12 weeks for up to 2 years, and then every 6 months thereafter.

Start Date30 Jan 2020

Sponsor / Collaborator

University of Wisconsin-Madison

[+3]

NCT03209869 / WithdrawnPhase 1IIT

Treatment of Relapsed or Refractory Neuroblastoma and Osteosarcoma With Ex-Vivo Expanded and Activated Haploidentical NK Cells and Hu14.18-IL2

Subjects with relapsed or refractory neuroblastoma and osteosarcoma will receive ex-vivo expanded and activated natural killer (NK) cells from a haploidentical donor in conjunction with the immunocytokine, hu14.18-IL2.

Start Date12 Mar 2018

Sponsor / Collaborator

University of Wisconsin-Madison

[+3]

NCT01334515 / CompletedPhase 2IIT

Feasibility/Phase II Study of hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients With Relapsed or Refractory Neuroblastoma

This phase II trial is studying how well hu14.18-interleukin-2 (IL2) fusion protein works when given together with sargramostim and isotretinoin in treating patients with relapsed or refractory neuroblastoma. Biological therapy, such as hu14.18-IL2 fusion protein, and sargramostim work in different ways to stimulate the immune system and stop tumor cells from growing. Drugs used in chemotherapy, such as isotretinoin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving hu14.18-IL2 fusion protein together with sargramostim and isotretinoin may kill more tumor cells.

Start Date01 Sep 2011

Sponsor / Collaborator

The Children's Oncology Group Foundation, Inc.

[+1]

100 Clinical Results associated with Lorukafusp alfa

100 Translational Medicine associated with Lorukafusp alfa

100 Patents (Medical) associated with Lorukafusp alfa

Literatures (Medical) associated with Lorukafusp alfa

01 Dec 2023·Cell reports

NK cells propagate T cell immunity following in situ tumor vaccination

Article

Author: Kim, KyungMann ; Newton, Michael A ; Jagodinsky, Justin C ; Berg, Tracy ; Clark, Paul A ; Morris, Zachary S ; Rakhmilevich, Alexander L ; Sondel, Paul M ; Erbe, Amy K ; Zuleger, Cindy L ; Ong, Irene M ; Vera, Jessica M ; Tetreault, Kaitlin ; Jin, Won Jong ; Le, Trang ; Albertini, Mark R

We report an in situ vaccination, adaptable to nearly any type of cancer, that combines radiotherapy targeting one tumor and intratumoral injection of this site with tumor-specific antibody and interleukin-2 (IL-2; 3xTx). In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8⁺ T cell effector polyfunctionality. This suggests the potential for 3xTx to promote antitumor immunity against metastatic tumors. In poorly immunogenic syngeneic murine melanoma or head and neck carcinoma models, 3xTx stimulates CD8⁺ T cell-mediated antitumor responses at targeted and non-targeted tumors. During 3xTx treatment, natural killer (NK) cells promote CTLA4⁺ regulatory T cell (T_reg) apoptosis in non-targeted tumors. This is dependent on NK cell expression of CD86, which is upregulated downstream of KLRK1. NK cell depletion increases T_reg infiltration, diminishing CD8⁺ T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8⁺ T cell immunity following 3xTx.

01 Sep 2022·Clinical cancer research : an official journal of the American Association for Cancer Research

Anti-GD2 Antibodies Conjugated to IL15 and IL21 Mediate Potent Antitumor Cytotoxicity against Neuroblastoma

Article

Author: Abbas, Shahroze ; Kelly, Michael C. ; Seibert, Charlie ; Zhang, Xiyuan ; Nguyen, Rosa ; Thiele, Carol J. ; Sun, Ming ; Shern, Jack F.

Abstract:

Purpose::

Half of the patients with high-risk neuroblastoma who receive GD2-targeted mAb do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to IL2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (IC) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 with hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma.

Experimental Design::

We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high neuroblastoma cell lines in vitro. T-cell–deficient mice with orthotopic patient-derived xenografts (PDX) and immunocompetent mice with transplantable orthotopic neuroblastoma were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq).

Results::

hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic neuroblastoma, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment.

Conclusions::

Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing neuroblastoma.

01 Jul 2020·Journal for immunotherapy of cancerQ2 · MEDICINE

In situ vaccination at a peripheral tumor site augments response against melanoma brain metastases

Q2 · MEDICINE

ArticleOA

Author: Carlson, Peter M ; Arthur, Ian S ; Lubin, Jonathan A ; Kler, Jasdeep ; Jagodinsky, Justin C ; Anderson, Bryce R ; Guy, Emily I ; Morris, Zachary S ; Clark, Paul A ; Kim, Kyung Mann ; Klar, Kelsey A ; Chakravarty, Ishan ; Heinze, Clinton M ; Kuo, John S ; Jin, Won Jong ; Bates, Amber M ; Le, Trang ; Sriramaneni, Raghava N ; Jaquish, Abigail A

Background:

Immune checkpoint inhibition (ICI) alone is not efficacious for a large number of patients with melanoma brain metastases. We previously established an in situ vaccination (ISV) regimen combining radiation and immunocytokine to enhance response to ICIs. Here, we tested whether ISV inhibits the development of brain metastases in a murine melanoma model.

Methods:

B78 (GD2+) melanoma ‘primary’ tumors were engrafted on the right flank of C57BL/6 mice. After 3–4 weeks, primary tumors were treated with ISV (radiation (12 Gy, day 1), α-GD2 immunocytokine (hu14.18-IL2, days 6–10)) and ICI (α-CTLA-4, days 3, 6, 9). Complete response (CR) was defined as no residual tumor observed at treatment day 90. Mice with CR were tested for immune memory by re-engraftment with B78 in the left flank and then the brain. To test ISV efficacy against metastases, tumors were also engrafted in the left flank and brain of previously untreated mice. Tumors were analyzed by quantitative reverse transcription-PCR, immunohistochemistry, flow cytometry and multiplex cytokine assay.

Results:

ISV+α-CTLA-4 resulted in immune memory and rejection of B78 engraftment in the brain in 11 of 12 mice. When B78 was engrafted in brain prior to treatment, ISV+α-CTLA-4 increased survival compared with ICI alone. ISV+α-CTLA-4 eradicated left flank tumors but did not elicit CR at brain sites when tumor cells were engrafted in brain prior to ISV. ISV+α-CTLA-4 increased CD8+ and CD4+ T cells in flank and brain tumors compared with untreated mice. Among ISV + α-CTLA-4 treated mice, left flank tumors showed increased CD8+ infiltration and CD8+:FOXP3+ ratio compared with brain tumors. Flank and brain tumors showed minimal differences in expression of immune checkpoint receptors/ligands or Mhc-1. Cytokine productions were similar in left flank and brain tumors in untreated mice. Following ISV+α-CTLA-4, production of immune-stimulatory cytokines was greater in left flank compared with brain tumor grafts.

Conclusion:

ISV augmented response to ICIs in murine melanoma at brain and extracranial tumor sites. Although baseline tumor-immune microenvironments were similar at brain and extracranial tumor sites, response to ISV+α-CTLA-4 was divergent with reduced infiltration and activation of immune cells in brain tumors. Additional therapies may be needed for effective antitumor immune response against melanoma brain metastases.

News (Medical) associated with Lorukafusp alfa

09 Apr 2024

·firstwordpharma.com

Essential Pharma gains neuroblastoma candidate through Renaissance buy

Essential Pharma announced on Tuesday that it acquired Renaissance Pharma for an undisclosed sum, gaining the latter's immunotherapy candidate, dubbed Hu14.18, which is in Phase II development for the treatment of high-risk neuroblastoma."Our acquisition of Hu14.18, the group's second product for treatment of a rare disease, and the first development-stage asset in our portfolio, is a significant milestone," remarked Essential CEO Emma Johnson. Hu14.18 "has already produced positive data in Phase II clinical trials, demonstrating a significant improvement in survival, and we are now committed to developing this immunotherapy to be able to bring it to market."A Phase II trial incorporating Hu14.18 into first-line therapy and within post-consolidation therapy for patients with high-risk neuroblastoma showed positive patient outcomes with 73.7% three-year event-free survival and 86% overall survival (OS). The trial is approaching the five-year OS readouts.Under the deal, Renaissance CEO Simon Ball will continue to work with Essential on the development of Hu14.18, as will many of the Renaissance team. Essential will work with St Jude Children’s Hospital in accordance with their 2023 exclusive license agreement to drive the development and commercialisation of Hu14.18 across the territories licensed to Renaissance. Essential will be responsible for clinical development of Hu14.18 along with defining the optimal route for regulatory approval and commercial launch of the immunotherapy.

Phase 2License out/inClinical ResultImmunotherapyAcquisition

09 Apr 2024

·www.biospace.com

Essential Pharma acquires Renaissance Pharma Ltd with its clinical stage immunotherapy for the treatment of high-risk neuroblastoma

Essential Pharma acquires Renaissance Pharma Ltd with its clinical stage immunotherapy for the treatment of high-risk neuroblastoma First development-stage asset to be added to the Essential Pharma portfolio and second product within rare disease Egham, UK – 9 April 2024 – Essential Pharma, an international specialty pharma group focused on ensuring that patients have sustainable access to low volume, clinically differentiated, niche pharmaceutical products across key therapeutic areas, announces that it has completed the acquisition of the entire issued share capital of Renaissance Pharma Ltd. Renaissance Pharma is a clinical stage pharmaceutical company focused on the development of life changing therapies in paediatric rare disease, with its lead asset being Hu14.18K322A (Hu14.18) – an immunotherapy currently in Phase II clinical development for the treatment of high-risk neuroblastoma (HRNB). The acquisition adds a second product candidate to Essential Pharma’s rare disease portfolio and underlines the group’s strategy of seeking out clinically differentiated medicines in small patient populations. This will be Essential’s first clinical development-stage asset and is targeted at addressing significant unmet needs in paediatric oncology patients. Simon Ball, CEO and co-founder of Renaissance Pharma, who has significant scientific and commercial expertise within the space, will continue to work with Essential Pharma on Hu14.18’s development, as will many of the Renaissance Pharma team. Neuroblastoma represents 7-10% of all childhood cancers and is the most common extracranial cancer in children and the most common cancer in children under one year of age12. Each year, more than 1500 people are diagnosed in Europe and 800 in the US23. Approximately half of all neuroblastoma patients have high risk (HRNB) disease which has an overall survival of ~50% over five years23. The current standard of care includes multiple cycles of chemotherapy, surgery, radiotherapy, stem cell transplantation and anti-GD2 monoclonal antibody (mAb) treatment2. There remains a significant unmet need in the availability of effective and suitable treatments for HRNB. A Phase II trial incorporating Hu14.18 into first-line therapy and additionally, within post-consolidation therapy for HRNB patients, demonstrated positive patient outcomes with 3-year event-free survival (EFS) of 73.7% and overall survival (OS) of 86.0%. Data from this study was published in the Journal of Clinical Oncology in December 2021 and is approaching five-year OS readouts4. Essential Pharma will work with St Jude Children’s Hospital in accordance with the exclusive license agreement that was signed between St Jude’s and Renaissance in 2023, in order to drive forward the development and commercialisation of Hu14.18 across the territories licensed to Renaissance. Essential Pharma will be responsible for clinical development and defining the optimal route for regulatory approval and eventual commercial launch of Hu14.18. Emma Johnson, CEO of Essential Pharma, commented: “Our acquisition of Hu14.18, the group’s second product for treatment of a rare disease, and the first development-stage asset in our portfolio, is a significant milestone for Essential Pharma, demonstrating our commitment to enabling access to clinically-differentiated medicines. Hu14.18 has enormous potential to help high risk neuroblastoma patients, the majority of whom are young children. It has already produced positive data in Phase II clinical trials, demonstrating a significant improvement in survival, and we are now committed to developing this immunotherapy to be able to bring it to market and to patients as quickly as possible.” Lee Morley, Executive Chairman, Renaissance Pharma Ltd, and Non-Executive Director, Essential Pharma, said: “Essential Pharma is the right partner to take Hu14.18 forward. Having worked alongside Emma at EUSA Pharma, a company specialising in oncology and rare disease, I know that she and the Essential Pharma team have the experience and expertise to bring this important product to market and make it available for children with high-risk neuroblastoma.” About Essential Pharma Essential Pharma is an international specialty pharmaceutical group dedicated to maintaining access to clinically differentiated, niche, branded medicines across multiple therapeutic areas. The group has been an important and valued partner to healthcare providers for over 20 years by giving underserved patient populations access to medicines that otherwise might not be available, and addressing clinical unmet needs. Essential Pharma operates globally in more than 70 countries, supplying a portfolio of products with a focus on the central nervous system (CNS), gastroenterology, ophthalmology, and rare disease. The group’s growth strategy is centred on portfolio optimisation and a targeted M&A approach to acquire commercial and late-clinical stage assets in the four therapeutic areas of focus. It is a trusted partner to multiple pharma companies of all sizes, with a proven history of integrating assets and managing complex technology transfers seamlessly while ensuring continuous and sustainable supply to patients. Essential Pharma is backed by Gyrus Capital, an investment firm dedicated to transformational investments in sectors with long-term sustainable growth, including healthcare. For more information, please visit essentialpharmagroup.com CONTACTS ICR Consilium Tracy Cheung/Chris Welsh/Isabelle Abdou Tel: +44 (0) 20 3709 5700 Email: Essentialpharma@consilium-comms.com 1 DuBois SG, Macy, ME, Henderson TO. High-Risk and Relapsed Neuroblastoma: Toward More Cures and Better Outcomes. American Society of Clinical Oncology Educational Book [Internet]. 2022 Jul;(42):768–80. Available from: 2 St. Jude Children’s Hospital. Neuroblastoma. Available from: 3 News Medical Life Sciences. European scientists target high-risk childhood cancer with liquid biopsy. Available from: 4 Furman WL, McCarville B, Shulkin BL, Davidoff A, Krasin M, Hsu CW, et al. Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. Journal of Clinical Oncology [Internet]. 2022 Feb 1;40(4):335–44. Available from:

Clinical ResultPhase 2ImmunotherapyLicense out/inAcquisition

100 Deals associated with Lorukafusp alfa

External Link

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Phase 2	US	Bristol Myers Squibb Co.	30 Jan 2020
Neuroblastoma recurrent	Phase 2	US	National Cancer Institute	01 Sep 2011
Neuroblastoma recurrent	Phase 2	CA	National Cancer Institute	01 Sep 2011
Refractory Neuroblastoma	Phase 2	US	National Cancer Institute	01 Sep 2011
Refractory Neuroblastoma	Phase 2	CA	National Cancer Institute	01 Sep 2011
Neuroblastoma	Phase 2	US	APEIRON Biologics AG	11 Aug 2005
Melanoma, Cutaneous Malignant	Phase 2	US	National Cancer Institute	01 May 2005
Osteosarcoma	Phase 1	US	National Cancer Institute	12 Mar 2018
GD2 Positive Glioma	Phase 1	US	National Cancer Institute	01 Oct 2001
GD2 Positive Glioma	Phase 1	AU	National Cancer Institute	01 Oct 2001

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00590824 (CO-05601 \| P163, CTgov)	Phase 2	-	23	Hu14.18-IL2 (Group A)	rncoosqcwo(zytaglfkcl) = cztfrarrgv anbhapcclx (oartwcylzu, dqodzhtcgt - zsolkaqevd) View more	-	22 Oct 2019
NCT00590824 (CO-05601 \| P163, CTgov)	Phase 2	-	23	Hu14.18-IL2 (Group B)	rncoosqcwo(zytaglfkcl) = gpzesagktx anbhapcclx (oartwcylzu, byhjulwhvw - qonmpiqmme) View more	-	22 Oct 2019
NCT01334515 (Pubmed \| Clin Cancer Res) Manual	Phase 2	Neuroblastoma	52	GMCSF+Isotretinoin+hu14.18-IL2	owdkltlkgn(dehlyxpqph) = expected and reversible nonhematologic toxicities pqaapgkjjl (bnuwjjlhfa ) View more	Positive	15 Oct 2019
NCT01334515 (CTgov)	Phase 2	Neuroblastoma recurrent \| Refractory Neuroblastoma	52	laboratory biomarker analysis+isotretinoin+sargramostim+hu14.18-IL2 fusion protein (Disease Measured by Standard Radiographic Criteria)	cxnzppqrgu(smdltwmjmu) = ruxrwdlkyr ggbdoklqfk (facuvwocmk, xckiaqdxmk - nirkqksogy) View more	-	20 Feb 2015
NCT01334515 (CTgov)	Phase 2	Neuroblastoma recurrent \| Refractory Neuroblastoma	52	laboratory biomarker analysis+isotretinoin+sargramostim+hu14.18-IL2 fusion protein (Disease Evaluable Only by I-MIBG or BM Histology)	cxnzppqrgu(smdltwmjmu) = whvbtmswhq ggbdoklqfk (facuvwocmk, pzfuaafvfs - mnhyphnqsv) View more	-	20 Feb 2015
NCT00082758 (CTgov)	Phase 2	Refractory Neuroblastoma	39	hu14.18-Interleukin-2 fusion protein (Disease Measurable by Standard Criteria(hu14.18-interleukin-2))	qteqhuvjan(womrcuxhfa) = bdujgprnfp ytofoflruo (kssonlcrku, bwffhgtppw - ideivpavuq) View more	-	16 Jan 2014
NCT00082758 (CTgov)	Phase 2	Refractory Neuroblastoma	39	hu14.18-Interleukin-2 fusion protein (Disease Eval by MIBG or BM Histology (hu14.18-interleukin-2))	qteqhuvjan(womrcuxhfa) = mroldkppid ytofoflruo (kssonlcrku, folaqkihxo - piuwujfskz) View more	-	16 Jan 2014
ASCO2012	Phase 2	Metastatic melanoma	14	hu14.18-IL2 6 mg/m^2/day	pahuiywzee(ysjcikhfmz) = zqhyibjojh trfmdwkqeo (afydsuopbp, 0.2% - 33.9%) View more	-	20 May 2012
ASCO2008	Phase 2	Neuroblastoma	39	hu14.18-IL2	fgyohemsex(rvijjhuoyv) = allergic reaction kmddemaadp (oynioyvghs ) View more	-	20 May 2008

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