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FDA approves anti-LAG-3 relatlimab-rmbw as part of a combination therapy for melanoma

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On March 18, 2022, Bristol Myers Squibb announced that Opdualag a fixed-dose combination of anti-PD-1 nivolumab and relatlimab-rmbw, administered as a single intravenous infusion, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Relatlimab (BMS-986016, ONO4482) is a human IgG4k antibody that targets LAG-3, which, like PD-1, is an immune checkpoint. Bristol Myers Squibb and Ono have a strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea, and Taiwan. An marketing authorization application is undergoing evaluation by the European Medicines Agency.

FDA’s approval was based on data from the Phase 2/3 RELATIVITY-047 trial (NCT03470922), which evaluated the effects of relatlimab combined with nivolumab versus nivolumab in a total of 714 patients with previously untreated metastatic or unresectable melanoma. Patients were randomized 1:1 and administered a fixed-dose combination of 160 mg relatlimab and 480 mg nivolumab or 480 mg nivolumab by intravenous infusion every 4 weeks until disease recurrence, unacceptable toxicity or withdrawal of consent. The study’s primary endpoint, progression-free survival (PFS) by blinded independent central review, was met. The median PFS in the group that received both relatlimab and nivolumab (n=355) was significantly longer (10.1 months [95% CI, 6.4–15.7]) than in the group that received nivolumab only (4.6 months [95% CI, 3.4–5.6]; hazard ratio: 0.75 [95% CI, 0.6–0.9]; P = 0.0055). [1]

1. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386:24-34.

Opdualag is the 4th antibody-based therapeutic granted a first approval for marketing in the EU or US in 2022. Explore our searchable table of antibody therapeutics approved in the EU or US for details.

Discovering and Targeting Neo-epitopes in Cancer

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Antibody Engineering & Therapeutics, held in December 2021, offered many opportunities to hear exciting and informative presentations by experts in the field. We are pleased to present here a summary of a plenary lecture by Prof. James Wells (USCF), kindly written by Dr. Czeslaw Radziejewski.

 


Discovering and Targeting Neo-epitopes in Cancer.
James Wells, Professor and Chair, Department of Pharmaceutical Chemistry, UCSF

Professor Wells presented the plenary lecture on the identification of cancer-associated proteolytic neo-epitopes in cell membrane proteins and the identification of novel cancer-specific MHC-1 peptide complexes. Cell surface proteins are the targets of most biologic and small molecule drugs. Professor Wells and colleagues use cell surface proteomics to examine changes in the cell surface proteins upon transformation with oncogenes such as KRAS, HER2, EGFR, BRAF, MEK, and Myc. Ecto-domains of identified proteins, which generally belong to the single pass trans-membrane class, are expressed as Fc fusion proteins and antibodies are generated against these proteins via screening phage libraries. Specificities of the antibodies are verified by testing against full-length trans-membrane proteins expressed by cells transfected with appropriate vectors.

Proteolysis is a primary post-translational modification of cell surface proteins. There are approximately 500 human proteases, and proteolysis plays an important role in disease progression, such as angiogenesis, invasion and metastasis, inflammation, and immune evasion. Well’s lab is exploring methods to identify proteolytic cleavage sites on the surfaceome of cancer cells.[1] To accomplish this, they devised a technology called N-terminomics, which uses the peptide ligase called subtiligase. Subtiligase ligates peptide esters to the N-terminus of a protein or a peptide. This enzyme can be used for other purposes, such as peptide cyclization and protein bioconjugation. The lab used peptides tagged with biotin or fluorescently labelled in conjunction with mass spectrometry to identify sites of proteolytic cleavage.[2,3] Prof. Wells showed an example of this strategy used to identify sites of cleavage by caspase in the proteome of a human cell line in which apoptosis was induced. This approach, however, identified only a limited number of cleaved proteins. In the next implementation of the strategy, cells were directly transfected with subtiligase. This strategy allowed the identification of hundreds of extracellular proteins that were proteolytically modified.

The newest strategy invented in Prof. Wells’ lab (unpublished) involves tethering subtiligase to glycans of cell surface proteins instead of transacting cells. Using this latest strategy in Kras-transformed cells, 611 cell surface cleavage events were observed. In HER2-transfected cells, 267 cleavage events were observed and the majority of events were not related to cleavage of signal peptide from extracellular proteins. Interestingly, the extent of proteolytic modification of some proteins in oncogene-transformed cells can either increase or decrease. Similarly, expression levels of the same proteins also change in both directions. N-terminomics of Kras- and HER2-transformed cells was thus different.

This study also identified an interesting protein called CDCP1, which has cleavage and expression that is upregulated in pancreatic cancer. The cleavage is indeed specific to cancer cells. Three closely nested cleavage sites were found in CDCP1. Antibodies (CL03.2) were developed in the lab against the cleaved form  of CDCP1. Cells containing the cleaved form were efficiently killed by the anti-CDCP1 antibody formatted as an antibody-drug conjugate (ADC). In Jurkat cells, an anti-CD3/anti-CDCP1 bispecific single-chain variable fragment showed killing activity. For in vivo studies, mouse-specific antibodies toward the truncated form of CDCP1 were generated and used to produce an auristatin (MMAF)-based ADC. An ADC against the truncated form of CDCp1 was well tolerated in non-tumor-bearing mouse, but the animals lost weight when treated with an ADC targeting the full-length protein. In a study of mice bearing xenograph tumors, the animals were administered antibody against the truncated form that was radiolabeled with isotope Lu 177 and a dramatic decrease of tumor growth was observed.

[Read more…]

Rare Disease Day, February 28, 2022

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Rare Disease Day is held to raise awareness of the more than 7,000 diseases that each affect a small number of people. In the US, any disease affecting fewer than 200,000 people (1 per ~1,650 people) is considered rare, while in Europe rare diseases ae defined as those that affect fewer than 1 in 2,000 people.

Regulatory agencies in the US, Europe, Japan, as well as other countries, have ‘orphan drug’ programs, which incentivize the development of drugs to treat rare diseases. Numerous monoclonal antibody (mAb) therapeutics have been granted Orphan Drug designations, as illustrated by the examples below.

Recently approved by FDA

Tebentafusp (KIMMTRAK®) for uveal melanoma

Approved by FDA in January 2022, tebentafusp-tebn is a bispecific fusion protein composed of: 1) a T cell receptor (TCR) recognizing a human leukocyte antigen (HLA)-A*02:01 complexed with a peptide derived from gp100 antigen expressed by melanoma cells, and 2) an antibody single-chain variable fragment that binds CD3 present on T cells. Developed by Immunocore, this molecule creates a bridge between tumor cells and immune cells, and thus facilitates tumor-cell killing by T cells. As the TCR domain recognizes a peptide presented on HLA-A*02:01, tebentafusp can only be used to treated patients expressing this HLA type. Tebentafusp was granted Breakthrough Therapy, Fast Track, and Orphan Drug designations by the FDA. Tebentafusp is marketed by Immunocore Holdings plc.

Sutimlimab (Enjaymo) for cold agglutinin disease

Sutimlimab-jome, a hinge-stabilized, humanized IgG4k antibody that targets and inhibits complement component 1s (C1s), was approved by FDA in February 2022 as a treatment of hemolysis in adult patients with cold agglutinin disease (CAD). A mutation in the Fc region (L235E) reduces the effector functions of the antibody. This rare autoimmune disorder is characterized by hemolysis caused by activation of the classic complement pathway. Sutimlimab received FDA’s Breakthrough Therapy and Orphan Drug designations for CAD, and Orphan Drug designation in the European Union for this indication. Sutimlimab is marketed by Sanofi.

Biological license applications in FDA review

Spesolimab (Boehringer Ingelheim) for generalized pustular psoriasis

Spesolimab is a humanized IgG1k antibody that blocks activation of the IL-36 receptor, which is involved in the pathogeneses of neutrophilic skin diseases such as generalized pustular psoriasis (GPP), palmoplantar pustulosis and hidradenitis suppurativa. FDA granted spesolimab Orphan Drug designation for the treatment of GPP. Marketing applications are undergoing evaluation by the FDA, as well as the European Medicines Agency (EMA).

Teclistamab (Janssen Research & Development, LLC) for multiple myeloma

Teclistamab (JNJ-64007957) is an IgG4l T-cell redirecting antibody derived from Ligand’s transgenic mouse (OmniAb) and Genmab’s DuoBody technology. The antibody selectively targets BCMA and CD3. Teclistamab was granted Breakthrough Therapy designation for the treatment of relapsed or refractory multiple myeloma (MM) by the FDA, and EMA’s PRIME designation for treatment of adult patients with relapsed or refractory MM who previously received ≥3 prior lines of therapy in 2021. Teclistamab had previously been granted Orphan Drug designations for MM in both the US and EU. Marketing applications are undergoing evaluation by the FDA and EMA.

BLA submission anticipated in Q1 2022

Mirvetuximab soravtansine (ImmunoGen, Inc.) for ovarian cancer   

Mirvetuximab soravtansine (IMGN853), comprising a humanized folate receptor alpha (FRα) IgG1k antibody conjugated to the maytansinoid drug DM4 via a cleavable disulfide linker, is being developed by ImmunoGen as a treatment for epithelial malignancies, including ovarian cancer adenocarcinoma. The drug has been granted US and EU Orphan Drug designations for ovarian cancer, as well as FDA’s Fast Track designation for a specific subset of patients with medium to high FRα-positive platinum-resistant ovarian cancer who received at least one, but no more than three prior systemic treatment regimens, and for whom single-agent chemotherapy is appropriate as the next line of therapy. ImmunoGen anticipates submission of a biologics license application in the first quarter of 2022, with potential accelerated approval in 2022.

Keep up to date on the late-stage pipeline and antibody therapeutic approvals all year by visiting our website!

More information about approved antibody therapeutics, including target, format and year of approval, can be found here.

More information about antibody therapeutics in late-stage studies can be found in ‘Antibodies to Watch in 2022‘ and in our searchable online table found here.

FDA issues emergency use authorization for bebtelovimab

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On February 11, 2022, the U.S. Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) for bebtelovimab (LY-CoV1404), an anti-SARS-CoV-2 monoclonal antibody that demonstrates neutralization against the Omicron variant. Bebtelovimab targets the SARS-CoV-2 spike glycoprotein receptor binding domain. The EUA was issued to Eli Lilly and Co.

The EUA for bebtelovimab is supported by clinical and nonclinical data. The clinical data are from a Phase 2, randomized, single-dose clinical trial (NCT04634409) evaluating the efficacy of bebtelovimab alone and bebtelovimab combined with other monoclonal antibodies for treating mild to moderate COVID-19.

Bebtelovimab is authorized for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. The authorized dose of bebtelovimab is 175 mg given as an intravenous injection over at least 30 seconds. A fact sheet for health care providers with additional information about bebtelovimab can be found here.

As previously announced, Lilly signed an agreement with the U.S. government to supply up to 600,000 doses of investigational drug bebtelovimab for at least $720 million.

FDA approves Enjaymo (sutimlimab-jome) for cold agglutinin disease

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On February 4, 2022, the US Food and Drug Administration (FDA) approved Enjaymo (sutimlimab-jome) infusion to decrease the need for red blood cell transfusion due to hemolysis in adults with cold agglutinin disease (CAD). This rare autoimmune disorder is characterized by hemolysis caused by activation of the classic complement pathway. Sponsored by Sanofi, sutimlimab is a hinge-stabilized, humanized IgG4k antibody that targets and inhibits complement component 1s (C1s). A mutation in the Fc region (L235E) reduces the effector functions of the antibody. Sutimlimab received FDA’s Breakthrough Therapy and Orphan Drug designations for CAD, and Orphan Drug designation in the EU for this indication.

The BLA was based on data from the CARDINAL open-label, single-arm study (NCT03347396), which enrolled 24 adult patients with CAD who received a recent blood transfusion. All participants received Enjaymo for up to six months and could choose to continue therapy in a second part of the trial. Based on body weight, participants received either a 6.5 g or 7.5 g infusion of Enjaymo on day 0, day 7, and every 14 days through week 25. In total, 54% of participants responded to Enjaymo. In this study, sutimlimab administration rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue.

The European Medicines Agency has accepted the submission of a Marketing Authorisation Application for sutimlimab.

Enjaymo is the 3rd antibody-based therapeutic granted a first approval for marketing in the EU or US in 2022. Explore our searchable table of antibody therapeutics approved in the EU or US for details.