Delving into the Latest Updates on Lorukafusp alfa with Synapse

Overview

Basic Info

Drug Type

Antibody fusion proteins

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+ [2]

Originator Organization

Lexigen Pharmaceuticals Corp.

Active Organization

APEIRON Biologics AGLexigen Pharmaceuticals Corp.

Inactive Organization

National Cancer Institute

Bristol Myers Squibb Co.

EMD Serono, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 45370L

Source: *****

Sequence Code 616720214H

Source: *****

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 1

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

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100 Translational Medicine associated with Lorukafusp alfa

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100 Patents (Medical) associated with Lorukafusp alfa

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33

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 ; Jagodinsky, Justin C ; Newton, Michael A ; Berg, Tracy ; Morris, Zachary S ; Clark, Paul A ; Rakhmilevich, Alexander L ; Sondel, Paul M ; Erbe, Amy K ; Zuleger, Cindy L ; Ong, Irene M ; Vera, Jessica M ; Jin, Won Jong ; Tetreault, Kaitlin ; 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. ; Shern, Jack F. ; Sun, Ming

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 Oct 2020·Journal for immunotherapy of cancerQ2 · MEDICINE

Intratumoral injection reduces toxicity and antibody-mediated neutralization of immunocytokine in a mouse melanoma model

Q2 · MEDICINE

ArticleOA

Author: Rakhmilevich, Alexander L ; Patel, Ravi B ; Bates, Amber M ; Erbe, Amy K ; Hoefges, Anna G ; Baniel, Claire C ; Morris, Zachary S ; Pieper, Alexander A ; Sondel, Paul M ; Hank, Jacquelyn A ; Sumiec, Elizabeth G

Background:

Some patients with cancer treated with anticancer monoclonal antibodies (mAbs) develop antidrug antibodies (ADAs) that recognize and bind the therapeutic antibody. This response may neutralize the therapeutic mAb, interfere with mAb effector function or cause toxicities. We investigated the potential influence of ADA to modify the tumor-binding capability of a tumor-reactive ‘immunocytokine’ (IC), namely, a fusion protein (hu14.18-IL2) consisting of a humanized, tumor-reactive, anti-GD2 mAb genetically linked to interleukin 2. We characterize the role of treatment delivery of IC (intravenous vs intratumoral) on the impact of ADA on therapeutic outcome following IC treatments in an established antimelanoma (MEL) regimen involving radiotherapy (RT) +IC.

Methods:

C57BL/6 mice were injected with human IgG or the hu14.18-IL2 IC to develop a mouse anti-human antibody (MAHA) response (MAHA+). In vitro assays were performed to assess ADA binding to IC using sera from MAHA+ and MAHA− mice. In vivo experiments assessed the levels of IC bound to tumor in MAHA+ and MAHA− mice, and the influence of IC route of delivery on its ability to bind to B78 (GD2+) MEL tumors.

Results:

MAHA is inducible in C57BL/6 mice. In vitro assays show that MAHA is capable of inhibiting the binding of IC to GD2 antigen on B78 cells, resulting in impaired ADCC mediated by IC. When B78-bearing mice are injected intravenously with IC, less IC binds to B78-MEL tumors in MAHA+ mice than in MAHA− mice. In contrast, when IC is injected intratumorally in tumor-bearing mice, the presence of MAHA does not detectibly impact IC binding to the tumor. Combination therapy with RT+IT-IC showed improved tumor regression compared with RT alone in MAHA+ mice. If given intratumorally, IC could be safely readministered in tumor-bearing MAHA+ mice, while intravenous injections of IC in MAHA+ mice caused severe toxicity. Histamine levels were elevated in MAHA+ mice compared with MAHA− mice after reintroduction of IC.

Conclusions:

Intratumoral injection may be a means of overcoming ADA neutralization of therapeutic activity of tumor-reactive mAbs or ICs and may reduce systemic toxicity, which could have significant translational relevance.

100 Deals associated with Lorukafusp alfa

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15443

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neuroblastoma recurrent	Phase 2	US	National Cancer Institute	01 Sep 2011
Neuroblastoma recurrent	Phase 2	CA	National Cancer Institute	01 Sep 2011
Melanoma	Phase 2	US	EMD Serono, Inc.	17 Dec 2007
Neuroblastoma	Phase 2	US	APEIRON Biologics AG	11 Aug 2005
Refractory Neuroblastoma	Phase 2	US	National Cancer Institute	01 Aug 2005
Refractory Neuroblastoma	Phase 2	CA	National Cancer Institute	01 Aug 2005
Melanoma, Cutaneous Malignant	Phase 2	US	National Cancer Institute	01 May 2005
GD2 Positive Glioma	Phase 1	US	National Cancer Institute	01 Oct 2001
GD2 Positive Glioma	Phase 1	AU	National Cancer Institute	01 Oct 2001
GD2 Positive Glioma	Phase 1	CA	National Cancer Institute	01 Oct 2001

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00590824 (CO-05601 \| P163, CTgov)	Phase 2	Melanoma	23	Hu14.18-IL2 (Group A)	xvoxoaefiq(cqrlrcvkuo) = iayzibzyat dtgamthotv (qfrxkabnyb, bobubylhtk - jluxqitfmr) View more	-	22 Oct 2019
NCT00590824 (CO-05601 \| P163, CTgov)	Phase 2	Melanoma	23	Hu14.18-IL2 (Group B)	xvoxoaefiq(cqrlrcvkuo) = yzymqpsyxv dtgamthotv (qfrxkabnyb, kxvydmkbpy - xrovxdejhb) View more	-	22 Oct 2019
NCT01334515 (Pubmed \| Clin Cancer Res) Manual	Phase 2	Neuroblastoma	52	GMCSF+Isotretinoin+hu14.18-IL2	gzldqihhwb(xamhzjecft) = expected and reversible nonhematologic toxicities cfadakmmuf (hrparkdsvu ) View more	Positive	15 Oct 2019
NCT00590824 (CO-05601, SITC2017)	Phase 2	Melanoma TILs -	23	hu14.18-IL2 treated tumors	cvlgbapate(xywheljnmo) = rhsswiotax vmgzrdtsrc (srxjxyihuo ) View more	Positive	07 Nov 2017
NCT00590824 (P163, SITC2016)	Phase 2	Melanoma GD2	-	hu14.18-IL2 6 mg/m2/d IV	qkskahcjnq(aiplxgyxwd) = cavwycudtk uwgfqezdem (gjmopqohic, 1.8 - not reached)	Positive	16 Nov 2016
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)	vgowlzhwxa(rxautqdzxu) = jsfufambnv jbljrbyjvb (rtwuhxbjur, qvhwgdmogk - dfwgynzmbn) 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)	vgowlzhwxa(rxautqdzxu) = klcmdukjit jbljrbyjvb (rtwuhxbjur, oqjwokhetr - fsdvpnzvxx) View more	-	20 Feb 2015
NCT00082758 (CTgov)	Phase 2	Refractory Neuroblastoma \| Neuroblastoma	39	hu14.18-Interleukin-2 fusion protein (Disease Measurable by Standard Criteria(hu14.18-interleukin-2))	biezffdjvx(enevobuksr) = ilednzdxix dpiydrwjco (unpotbpjme, penrmgudkd - ppjqmngjtq) View more	-	16 Jan 2014
NCT00082758 (CTgov)	Phase 2	Refractory Neuroblastoma \| Neuroblastoma	39	hu14.18-Interleukin-2 fusion protein (Disease Eval by MIBG or BM Histology (hu14.18-interleukin-2))	biezffdjvx(enevobuksr) = gvdvgybwye dpiydrwjco (unpotbpjme, pfuifunzyy - woxuhlbskx) View more	-	16 Jan 2014
ASCO2012	Phase 2	Metastatic melanoma	14	hu14.18-IL2 6 mg/m^2/day	ihmqgkrbdb(ctcfritwqh) = ybgyyujuwm jemjkdinyg (qrrubxnlkc, 0.2% - 33.9%) View more	-	20 May 2012
Pubmed \| J Clin Oncol	Phase 2	Neuroblastoma GD2 disialoganglioside	-	hu14.18-IL2	gxdsfwfcdz(xjykoorxbn) = Grade 3 and 4 nonhematologic toxicities included capillary leak, hypoxia, pain, rash, allergic reaction, elevated transaminases, and hyperbilirubinemia. Two patients required dopamine for hypotension, and one patient required ventilatory support for hypoxia. Most toxicities were reversible within a few days of completing a treatment course and were expected based on phase I results. mylopdpccd (qusvplyveo )	-	20 Nov 2010
ASCO2008	Phase 2	Neuroblastoma	39	hu14.18-IL2	tyrfakqwip(zzfvologfn) = allergic reaction flpejfwujn (qsnkmtrvyb ) View more	-	20 May 2008
NCT00003750 (Pubmed \| Clin Cancer Res)	Phase 1	Melanoma \| Neuroblastoma	27	hu14.18-IL2	isghjvkdxi(liejnqndrk) = hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia ggjsaatytl (buwdbfkrhd ) View more	-	15 Mar 2006