scholarly journals Engineering IgG-Like Bispecific Antibodies—An Overview

Antibodies ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 28 ◽  
Author(s):  
Simon Krah ◽  
Harald Kolmar ◽  
Stefan Becker ◽  
Stefan Zielonka
Keyword(s):  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Malignant Ascites ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Clotting Factors ◽  
Effector Functions ◽  
Antibody Therapeutics ◽  
Complement Dependent Cytotoxicity ◽  
Therapeutic Concepts

Monoclonal antibody therapeutics have proven to be successful treatment options for patients, which have various indications. Particularly in oncology, therapeutic concepts involving antibodies often rely on the so-called effector functions, such as antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC), which are programed in the antibody Fc region. However, Fc-mediated effector mechanisms often seem to be insufficient in properly activating the immune system to act against tumor cells. Furthermore, long term treatments can lead to resistance against the applied drug, which is monospecific by nature. There is promise in using specific antibodies to overcome such issues due to their capability of recruiting and activating T-cells directly at the tumor site, for instance. During the last decade, two of these entities, which are referred to as Blinatumomab and Catumaxomab, have been approved to treat patients with acute lymphoblastic leukemia and malignant ascites. In addition, Emicizumab, which is a bispecific antibody targeting clotting factors IXa and X, was recently granted market approval by the FDA in 2017 for the treatment of hemophilia A. However, the generation of these next generation therapeutics is challenging and requires tremendous engineering efforts as two distinct paratopes need to be combined from two different heavy and light chains. This mini review summarizes technologies, which enable the generation of antibodies with dual specificities.

scholarly journals How I treat relapsed acute lymphoblastic leukemia in the pediatric population

Blood ◽  
2020 ◽  
Vol 136 (16) ◽  
pp. 1803-1812 ◽  
Author(s):  
Stephen P. Hunger ◽  
Elizabeth A. Raetz
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Population ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Survival Rates ◽  
Treatment Decision ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
The Past

Abstract Relapsed acute lymphoblastic leukemia (ALL) has remained challenging to treat in children, with survival rates lagging well behind those observed at initial diagnosis. Although there have been some improvements in outcomes over the past few decades, only ∼50% of children with first relapse of ALL survive long term, and outcomes are much worse with second or later relapses. Recurrences that occur within 3 years of diagnosis and any T-ALL relapses are particularly difficult to salvage. Until recently, treatment options were limited to intensive cytotoxic chemotherapy with or without site-directed radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). In the past decade, several promising immunotherapeutics have been developed, changing the treatment landscape for children with relapsed ALL. Current research in this field is focusing on how to best incorporate immunotherapeutics into salvage regimens and investigate long-term survival and side effects, and when these might replace HSCT. As more knowledge is gained about the biology of relapse through comprehensive genomic profiling, incorporation of molecularly targeted therapies is another area of active investigation. These advances in treatment offer real promise for less toxic and more effective therapy for children with relapsed ALL, and we present several cases highlighting contemporary treatment decision-making.

scholarly journals European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma

Haematologica ◽  
2021 ◽  
Author(s):  
Benedetto Bruno ◽  
Ralph Wäsch ◽  
Monika Engelhardt ◽  
Francesca Gay ◽  
Luisa Giaccone ◽  
...  
Keyword(s):  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Treatment Resistance ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Cell Therapies ◽  
Management Of Complications ◽  
Car T

Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.

scholarly journals Protease-Activation of Fc-Masked Therapeutic Antibodies to Alleviate Off-Tumor Cytotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Adrian Elter ◽  
Desislava Yanakieva ◽  
David Fiebig ◽  
Kerstin Hallstein ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Therapeutic Antibodies ◽  
Antibody Isotype ◽  
Effector Functions ◽  
Antibody Therapeutics ◽  
Drug Conjugates ◽  
Complement Dependent Cytotoxicity ◽  
Fold Reduction ◽  
New Strategy ◽  
Protease Activation ◽  
Dependent Cell

The interaction of the Fc region of therapeutic antibodies and antibody-drug conjugates with Fcγ receptors (FcγRs) can lead to unpredictable and severe side effects. Over the last decades several strategies have been developed to overcome this drawback, including extensive Fc- and glycoengineering and antibody isotype switching. However, these approaches result in permanently Fc-silenced antibody derivates which partially or completely lack antibody-mediated effector functions. Nevertheless, for a majority of antibody-based drugs, Fc-mediated effector functions, like antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP) as well as complement-dependent cytotoxicity (CDC), represent the most substantial modes of action. We argued that a new strategy combining the beneficial properties of Fc-silencing and controlled activation of effector functions can pave the way to potent antibody therapeutics, reducing the FcγRs-mediated off-target toxicity. We present a novel Fc-tamed antibody format, where the FcγR-binding sites of antibodies are blocked by anti-isotypic masking units, hindering the association of FcγR and complement component 1 (c1q) to the Fc domain. The masking units were genetically fused to trastuzumab, including a protease-addressable peptide-liker. Our Fc-tamed antibodies demonstrated completely abolished interaction to soluble high-affinity Fcγ-Receptor I and c1q. In reporter cell-based ADCC assays, our Fc-tamed antibodies exhibited a 2,700 to 7,100-fold reduction in activation, compared to trastuzumab. Upon demasking by a tumor-associated protease, the Fc-activated antibodies demonstrated restored FcγR-binding, c1q-binding and the ability to induce potent ADCC activation. Furthermore, cell killing assays using donor-derived NK cells were performed to validate the functionality of the Fc-tamed antibody variants. To our knowledge, this approach represents the first non-permanently Fc-silenced antibody, which can be re-activated by a tumor-associated protease, eventually extending the field of novel antibody formats.

scholarly journals Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 387 ◽  
Author(s):  
Nikolai Siebert ◽  
Sascha Troschke-Meurer ◽  
Madlen Marx ◽  
Maxi Zumpe ◽  
Karoline Ehlert ◽  
...  
Keyword(s):  
High Risk ◽  
Pain Intensity ◽  
Interleukin 2 ◽  
Phase 2 ◽  
Strong Reduction ◽  
Treatment Toxicity ◽  
Effector Functions ◽  
Phase 2 Trial ◽  
Complement Dependent Cytotoxicity

GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d; d8–18) combined with s.c. IL-2 (6 × 106 IU/m2/d; d1–5, d8–12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 ± 0.50 µg/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.

Towards Effective Immunotherapy of Multiple Myeloma: Enhanced Elimination of Myeloma Cells by Combination of Lenalidomide with the Human CD38 Monoclonal Antibody Daratumumab

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3059-3059
Author(s):  
Michael S. van der Veer ◽  
Michel de Weers ◽  
Berris van Kessel ◽  
Shulamiet Wittebol ◽  
Joost M Bakker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Ex Vivo ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Long Term Outcomes ◽  
Effector Cells ◽  
Complement Dependent Cytotoxicity ◽  
Potential Benefits ◽  
Pre Treatment

Abstract Abstract 3059 Since its approval by the FDA, lenalidomide (LEN) demonstrates impressive results in patients with newly-diagnosed and relapsed multiple myeloma (MM). Despite these improvements, MM remains incurable, and new innovative treatments need to be developed in efforts to improve long term outcomes. Recently we have developed a new human CD38 antibody, daratumumab (DARA) which mediates MM cell killing via complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and apoptosis. In the current study we evaluated the potential benefits of combining lenalidomide (LEN) with daratumumab (DARA). We demonstrate that DARA-dependent ADCC of purified primary MM cells, as well as of CD38+ UM 9 MM cells was significantly augmented by pre-treatment of PBMC effector cells with LEN. Importantly, a synergism between LEN and DARA was observed in ex-vivo assays, which allowed us to investigate ADCC directly in whole BM-MNC, thus without isolating MM cells from their natural environment. Interestingly, DARA-induced ADCC was significantly upregulated in PBMC derived from three MM patients who were undergoing LEN treatment. In conclusion, these results support the hypothesis that powerful and complementary effects may be achieved by combining LEN and DARA in clinical MM management. Disclosures: Veer: GenMab, Utrecht: Research Funding. Weers:Genmab: Employment. Bakker:GenMab, Utrecht, Netherlands: Employment. Parren:Genmab: Employment. Lokhorst:GenMab: Research Funding. Mutis:GenMab: Research Funding.

Új lehetőségek a refrakter és relabált Hodgkin-lymphomás betegek kezelésében

2015 ◽  
Vol 156 (45) ◽  
pp. 1824-1833 ◽  
Author(s):  
Árpád Illés ◽  
Ádám Jóna ◽  
Zsófia Simon ◽  
Miklós Udvardy ◽  
Zsófia Miltényi
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Treatment Options ◽  
Survival Rates ◽  
Relapse Free Survival ◽  
Term Survival ◽  
Free Survival ◽  
Novel Treatment ◽  
Refractory Hodgkin Lymphoma

Introduction: Hodgkin lymphoma is a curable lymphoma with an 80–90% long-term survival, however, 30% of the patients develop relapse. Only half of relapsed patients can be cured with autologous stem cell transplantation. Aim: The aim of the authors was to analyze survival rates and incidence of relapses among Hodgkin lymphoma patients who were treated between January 1, 1980 and December 31, 2014. Novel therapeutic options are also summarized. Method: Retrospective analysis of data was performed. Results: A total of 715 patients were treated (382 men and 333 women; median age at the time of diagnosis was 38 years). During the studied period the frequency of relapsed patients was reduced from 24.87% to 8.04%. The numbers of autologous stem cell transplantations was increased among refracter/relapsed patients, and 75% of the patients underwent transplantation since 2000. The 5-year overall survival improved significantly (between 1980 and 1989 64.4%, between 1990 and 1999 82.4%, between 2000 and 2009 88.4%, and between 2010 and 2014 87.1%). Relapse-free survival did not change significantly. Conclusions: During the study period treatment outcomes improved. For relapsed/refractory Hodgkin lymphoma patients novel treatment options may offer better chance for cure. Orv. Hetil., 2015, 156(45), 1824–1833.

Antiretroviral Treatment-Associated Labia Majora Lipohypertrophy: A Rare Case and Plastic Surgical Treatment Options

2017 ◽  
Vol 2 (1) ◽  
pp. 43
Author(s):  
Akmal Hisham ◽  
Devananthan Ilenghoven ◽  
Wan Syazli Wan Ahmad Kamal ◽  
Salina Ibrahim ◽  
Shah Jumaat Mohd Yussof
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
Daily Living ◽  
Treatment Options ◽  
Hiv Positive ◽  
Highly Active ◽  
Labia Majora ◽  
The Face ◽  
Central Fat

The emergence of highly active antiretroviral therapy (HAART) has revolutionized the prognosis of HIV-infected patients. However, the extended use of HAART is associated with a disfiguring complication termed lipodystrophy, a disorder of body fat maldistribution causing peripheral fat loss (lipoatrophy) and central fat accumulation (lipohypertrophy). Lipoatrophy commonly affects the face, legs, buttocks and arm, whilst lipohypertrophy frequently favours the abdomen, breast and dorsocervical region. To our knowledge, we present only the second documented case in the literature of a labia majora lipohypertrophy in a HIV-positive patient receiving long-term HAART. The severity of labial abnormality caused significant physical and functional morbidities. Labiaplasty with dermolipectomy of the labia majora and excisional lipectomy of the mons pubis was successfully performed. At a 6-month follow-up, patient had no recurrence with resolution of symptoms and resumption of normal activities of daily living (ADL).

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