Fully synthetic platform to rapidly generate tetravalent bispecific nanobody-based immunoglobulins.

Nanobodies bind a target antigen with a kinetic profile similar to a conventional antibody, but exist as a single heavy chain domain that can be readily multimerized to engage antigen via multiple interactions. Presently, most nanobodies are produced by immunizing camelids; however, platforms for animal-free production are growing in popularity. Here, we describe the development of a fully synthetic nanobody library based on an engineered human VH3-23 variable gene and a multispecific antibody-like format designed for biparatopic target engagement. To validate our library, we selected nanobodies against the SARS-CoV-2 receptor-binding domain and employed an on-yeast epitope binning strategy to rapidly map the specificities of the selected nanobodies. We then generated antibody-like molecules by replacing the VH and VL domains of a conventional antibody with two different nanobodies, designed as a molecular clamp to engage the receptor-binding domain biparatopically. The resulting bispecific tetra-nanobody immunoglobulins neutralized diverse SARS-CoV-2 variants with potencies similar to antibodies isolated from convalescent donors. Subsequent biochemical analyses confirmed the accuracy of the on-yeast epitope binning and structures of both individual nanobodies, and a tetra-nanobody immunoglobulin revealed that the intended mode of interaction had been achieved. This overall workflow is applicable to nearly any protein target and provides a blueprint for a modular workflow for the development of multispecific molecules.

A neutralizing bispecific single-chain antibody against SARS-CoV-2 Omicron variant produced based on CR3022.

Introduction: The constantly mutating SARS-CoV-2 has been infected an increasing number of people, hence the safe and efficacious treatment are urgently needed to combat the COVID-19 pandemic. Currently, neutralizing antibodies (Nabs), targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are potentially effective therapeutics against COVID-19. As a new form of antibody, bispecific single chain antibodies (BscAbs) can be easily expressed in E. coli and exhibits broad-spectrum antiviral activity. Methods: In this study, we constructed two BscAbs 16-29, 16-3022 and three single chain variable fragments (scFv) S1-16, S2-29 and S3022 as a comparison to explore their antiviral activity against SARS-CoV-2. The affinity of the five antibodies was characterized by ELISA and SPR and the neutralizing activity of them was analyzed using pseudovirus or authentic virus neutralization assay. Bioinformatics and competitive ELISA methods were used to identify different epitopes on RBD. Results: Our results revealed the potent neutralizing activity of two BscAbs 16-29 and 16-3022 against SARS-CoV-2 original strain and Omicron variant infection. In addition, we also found that SARS-CoV RBD-targeted scFv S3022 could play a synergistic role with other SARS-CoV-2 RBD-targeted antibodies to enhance neutralizing activity in the form of a BscAb or in cocktail therapies. Discussion: This innovative approach offers a promising avenue for the development of subsequent antibody therapies against SARSCoV-2. Combining the advantages of cocktails and single-molecule strategies, BscAb therapy has the potential to be developed as an effective immunotherapeutic for clinical use to mitigate the ongoing pandemic.

Evolution of Clinical Trials in Oncohematology in a Reference Center: Does It Worth a Dedicated Structure?

Introduction: As part of the reorganization of our outpatient activity in onco-hematology (OH), questions were raised about the relevance of dedicating a specific structure to clinical research in this field. These questions arise all the more so as the proportion of OH clinical trials (CT) in our center has increased from 10% to 45% of all CT between 2000 and 2020. The aim of this study is to assess the evolution of this activity and thus to consider the interest of such a structure. Material(s) and Method(s): A retrospective data review of new CT related to OH in our center from 2016 to 2021 was performed. The evolution of 3 key indicators was assessed: distribution of OH CT among all CT, main OH indications and preferred routes of administration. Results and discussion: Over the period 2016-2021, OH CT represented an average of 32% of newly activated CT corresponding to 34% in 2016 and 48% in 2021 (approximately 90 CT start each year for a total of 420 CT in our center). A short decrease was observed in 2019 and 2020, 25% and 24% respectively, probably related to Covid-19. In terms of sterile preparations, OH represented steadily more than 60% of our activity over the period. The main indications were lymphomas (30%), acute myeloid leukemias (AML - 19%), myelodysplastic syndromes (12%) and CT related to transplant center (12%) in steady distribution overtime. Only new CT in myeloma increased from 7% to 18% in relation with increased subcutaneous (SC) use of daratumumab. Regarding preferred routes of administration, an increased trend in oral and SC routes is observed (respectively 53% and 7% in 2016 vs. 69%and 28% in 2021). The increasing use of SC intensified in 2017 as part of the arrival of AML treatments combining azacitidine (SC) with venetoclax (oral). New CT using the intravenous route decreased from 70% in 2016 to 51% in 2021 even if bispecific antibodies araised in 2021. Focusing in 2021, 1359 visits (772 in day hospital for protocol chemotherapy and 597 for oral treatment) were observed, i.e. 6 patients per day. Conclusion(s): This review showed OH's activity growth in our center. The increasingly frequent use of SC and oral routes requires that patients be fully informed and trained about their own management. In this context, a pharmacist has its place and could best inform patients about the adverse effects of new complex therapies (antibodies, targeted therapy). A unique place, organized and dedicated to clinical research in OH, would allow patients benefiting from a structured and exhaustive support as well as meeting all the healthcare professionals involved and finally ensuring the conditions for optimal care.

Novel bispecific human antibody platform specifically targeting a fully open spike conformation potently neutralizes multiple SARS-CoV-2 variants.

Rapid emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted an urgent need for the development of broadly applicable and potently neutralizing antibody platform against the SARS-CoV-2, which can be used for combatting the coronavirus disease 2019 (COVID-19). In this study, based on a noncompeting pair of phage display-derived human monoclonal antibodies (mAbs) specific to the receptor-binding domain (RBD) of SARS-CoV-2 isolated from human synthetic antibody library, we generated K202.B, a novel engineered bispecific antibody with an immunoglobulin G4-single-chain variable fragment design, with sub- or low nanomolar antigen-binding avidity. Compared with the parental mAbs or mAb cocktail, the K202.B antibody showed superior neutralizing potential against a variety of SARS-CoV-2 variants in vitro. Furthermore, structural analysis of bispecific antibody-antigen complexes using cryo-electron microscopy revealed the mode of action of K202.B complexed with a fully open three-RBD-up conformation of SARS-CoV-2 trimeric spike proteins by simultaneously interconnecting two independent epitopes of the SARS-CoV-2 RBD via inter-protomer interactions. Intravenous monotherapy using K202.B exhibited potent neutralizing activity in SARS-CoV-2 wild-type- and B.1.617.2 variant-infected mouse models, without significant toxicity in vivo. The results indicate that this novel approach of development of immunoglobulin G4-based bispecific antibody from an established human recombinant antibody library is likely to be an effective strategy for the rapid development of bispecific antibodies, and timely management against fast-evolving SARS-CoV-2 variants.

Targeted Treatment of Relapsed or Refractory Follicular Lymphoma: Focus on the Therapeutic Potential of Mosunetuzumab.

Follicular lymphoma is the most common indolent non-Hodgkin's lymphoma, and because of the incurable nature of this disorder, new therapies are constantly needed. The recently approved T-cell-dependent bispecific antibody mosunetuzumab showed promising results and manageable toxicities for patients with relapsed or refractory follicular lymphoma. Namely, as opposed to cellular immunotherapy options, this agent has the potential of being effective in patients with unfavorable features with a tolerable rate and severity of cytokine release syndrome, immune effector cell-associated neurotoxicity, and infectious complications. Given the recent withdrawal from the market of PI3K inhibitors and the practical challenges in utilizing with chimeric antigen receptor T-cells (CAR-T) for some patients, mosunetuzumab represents a "breath of fresh air" for both patients and hemato-oncologists. More data are required to better define the real potential of this molecule, either alone or in combination with other agents, including antibody drug conjugates, immunomodulators, and checkpoint inhibitors. Future studies will also shed light on the efficacy of mosunetuzumab compared with CAR-T, in well-designed registries or ideally in randomized controlled trials.

Comparative Assessment of the Binding and Neutralisation Activity of Bispecific Antibodies Against SARS-CoV-2 Variants.

Background: Neutralising antibodies against SARS-CoV-2 are a vital component in the fight against COVID-19 pandemic, having the potential of both therapeutic and prophylactic applications. Bispecific antibodies (BsAbs) against SARS-CoV-2 are particularly promising, given their ability to bind simultaneously to two distinct sites of the receptor-binding domain (RBD) of the viral spike protein. Such antibodies are complex molecules associated with multi-faceted mechanisms of action that require appropriate bioassays to ensure product quality and manufacturing consistency. Methods: We developed procedures for biolayer interferometry (BLI) and a cell-based virus neutralisation assay, the focus reduction neutralisation test (FRNT). Using both assays, we tested a panel of five BsAbs against different spike variants (Ancestral, Delta and Omicron) to evaluate the use of these analytical methods in assessing binding and neutralisation activities of anti-SARS-CoV-2 therapeutics. Results: We found comparable trends between BLI-derived binding affinity and FRNT-based virus neutralisation activity. Antibodies that displayed high binding affinity against a variant were often followed by potent neutralisation at lower concentrations, whereas those with low binding affinity also demonstrated reduced neutralisation activity. Conclusion: The results support the utility of BLI and FRNT assays in measuring variant-specific binding and virus neutralisation activity of anti-SARS-CoV-2 antibodies.

An Engineered IgG-VHH Bispecific Antibody against SARS-CoV-2 and Its Variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies are shown to be effective therapeutics for providing coronavirus disease 2019 (COVID-19) protection. However, recurrent variants arise and facilitate significant escape from current antibody therapeutics. Bispecific antibodies (bsAbs) represent a unique platform to increase antibody breadth and to reduce neutralization escape. Herein, a novel immunoglobulin G-variable domains of heavy-chain-only antibody (IgG-VHH) format bsAb derived from a potent human antibody R15-F7 and a humanized nanobody P14-F8-35 are rationally engineered. The resulting bsAb SYZJ001 efficiently neutralizes wild-type SARS-CoV-2 as well as the alpha, beta, gamma, and delta variants, with superior efficacy to its parental antibodies. Cryo-electron microscopy structural analysis reveals that R15-F7 and P14-F8-35 bind to nonoverlapping epitopes within the RBD and sterically hindered ACE2 receptor binding. Most importantly, SYZJ001 shows potent prophylactic and therapeutic efficacy against SARS-CoV-2 in three established mouse models. Collectively, the current results demonstrate that the novel bsAb format is feasible and effective, suggesting great potential as an inspiring antiviral strategy.

Human monoclonal antibodies to the spike subdomain 1 neutralize SARS-CoV-2 and its variants of concern

Progress in the fight against COVID-19 is jeopardized by the emergence of SARS-CoV-2 variants that diminish or abolish the efficacy of vaccines and antiviral monoclonal antibodies. Novel immune therapies are therefore needed, that are broadly effective against present and future coronavirus threats. In principle, this could be achieved by focusing on portions of the virus that are both functionally relevant and averse to change. The Subdomain 1 (SD1) of SARS-CoV-2 Spike protein is adjacent to the RBD and its sequence is conserved across SARS-CoV-2 variants, except for substitutions A570D in Alpha (B.1.1.7) and T547K in Omicron BA.1 (B.1.1.529). In order to specifically identify and study human antibodies targeting SD1, we designed a flow cytometry-based strategy that combines negative selection of B cells binding to the Receptor Binding Domain (RBD) with positive selection of those binding to SD1-RBD fusion protein. Among the 15 produced human monoclonal antibodies, 6 are SD1-specific. 3 of them cross-react with SD1-RBDs corresponding to all six variants of concern and 2 are neutralizing SARS-CoV-2 pseudovirus. Antibody sd1.040 also neutralizes Delta, Omicron BA.1 and Omicron BA.2 pseudovirus, synergizes with an antibody to the RBD for neutralization, and protects mice when present in a bispecific antibody. Thus, naturally occurring antibodies can neutralize SARS-CoV-2 variants by binding to SD1 and can act synergistically against SARS-CoV-2 in preclinical models.

MANAGEMENT OF RELAPSED / REFRACTORY (R/R) B-CELL NON HODGKIN LYMPHOMA (B-NHL) WITH ANTI-CD20XCD3 BISPECIFIC ANTIBODY GLOFITAMAB. A SINGLE CENTER EXPERIENCE

Background: Prognosis of r/r B-NHL is detrimental. Potentially curative therapeutic approaches, such as autologous stem cell transplantation and innovative CAR-T cell therapy, require maximum disease control to achieve optimal results. Glofitamab is a new bispecific antibody, with a unique 2:1 molecular configuration resulting in superior potency compared with other CD20xCD3 bispecific antibodies with a 1:1 format. Aims: Based on these encouraging results, we included 5 heavily pretreated patients in the early access program of Glofitamab, available in our country. Methods: We collected the data of 5 consecutive patients with r/r B-NHL, who were treated with Glofitamab in our department during the last 15 months. Results: Three men and 2 women, median age of 57 years (38-62), were resistant to 4 (n = 3) and 5 (n = 2) previous lines of treatment. The underlying lymphoma was Richter's transformation of CLL after allogeneic transplantation (alloHSCT), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), r/r diffuse large B-cell lymphoma (DLBCL) after CAR-T therapy and gray zone lymphoma (GZL) transformed to DLBCL. The median number of Glofitamab cycles administered was 3 (2-7). All 5 patients responded early to treatment, which became apparent immediately after the first dose of 2.5 mg. The patient with Richter's syndrome achieved metabolic remission after the 4th cycle and underwent second alloHSCT after the 7th cycle. Unfortunately, he passed away 8 months after alloHSCT due to disseminated atypical mycobacterial infection, remaining however disease free. The patient with tFL also achieved metabolic remission, but the drug was discontinued after the 7th cycle due to COVID-19 infection. He died two months after Glofitamab interruption due to disease progression and CMV encephalitis. The patient with PMBCL, responded partially after Glofitamab and had mediastinal radiotherapy as bridging therapy to CAR-T therapy. As the latter was delayed due to CMV reactivation and CMV enteritis, our patient deceased due to progressive disease. The patient with DLBCL after CAR-T therapy had initial clinical response after two Glofitamab cycles. Due to severe COVID-19, we decided to hold Glofitamab. COVID-19 and disease progression led to his death, a few weeks after COVID-19 diagnosis. Finally, the patient with transformed GZL had Glofitamab administered as bridging therapy prior to CAR-T treatment. After 3 cycles, while she was prepared to proceed to CAR-T therapy, she was diagnosed with invasive aspergillosis. She is currently been treated with antifungal agents, whereas disease is still active. Cytokine release syndrome (CRS) occurred in 3 out of 5 patients. In all cases it was grade 1-2 and manifested at the first administration of the drug, after 4, 32 and 10 hours respectively, from infusion initiation. CRS was managed with antipyretics and steroids, whereas none patient required Intensive Care Unit support. Only one patient required tocilizumab. No Immune effector cell-Associated Neurotoxicity Syndrome (ICANS) was observed. Summary/Conclusion: Glofitamab is effective in treating patients with r/r aggressive B-cell NHL. Efficacy makes it an appropriate bridging tool to autologous, alloHSCT or CAR-T therapy. Nevertheless, relapse remains a challenge for r/r disease. Adverse events, such as CRS, were generally manageable. Given the fact that it was administered to heavily pretreated patients, caution to opportunistic pathogens should be paid. Indeed, toxicity profile may be proven to be more favorable if the agent is being administered earlier in therapeutic algorithms.

Kinetics of humoral immunodeficiency with bispecific antibody therapy in multiple myeloma

Background: Bispecific antibodies (bsAb) are a promising class of therapeutics in RRMM. While hypogammaglobinemia (HGG) is anticipated due to plasma cell depletion, there is a lack of information about the degree of secondary immunodeficiency and resultant infectious complications. We investigated the kinetics of HGG in patients with RRMM on bsAb therapy. Methods: We identified and followed 42 patients treated on early clinical trials of bsAb at our institution between 2019 and 2021. Serial immunoglobulin levels and infections were obtained from the start of therapy until last follow up or 3 months after study exit. Results: 49 treatment courses were included from 42 individual patients. All patients were triple class exposed with a median of 5 prior lines of therapy. The median age was 67 (44-85) years, with 49% females. African Americans accounted for 18% of patients. 96% of patients had at least one prior ASCT. 90% of patients received bsAb targeting BCMA including 7 patients who received more than one line of BCMA targeting therapies. At a median follow up 9.5 (0.9-28.6) months, 40.8% of patients remained on bsAb therapy. At the start of therapy, the median IgG, IgA, and IgM levels were 560 (44-9436), 15 (5-3886) and 6 (5-64) mg/dL, respectively and 50% of patients had severe HGG (≤400mg/dl). Serum IgG levels reached a nadir at 3 months while, IgA and IgM at 1 month, from the start of therapy. The median nadir levels of IgG were 159 (40-2996) mg/dL, while it was < 5 mg/dL for both IgA and IgM. IgG levels were below the detectable range (< 40 mg/dl) in 28% of patients at some point during therapy. IgA and IgM were also below the detectable range (< 5 mg/dl) in 50% and 60% of patients, respectively. At last follow-up, the median IgG levels were 444 (40-1860) mg/dL and IgA 5 (5-254) mg/dL and IgM 5 (5-44) mg/dL. Additionally, 38% of patients remained severely hypogammaglobinemic. 57% (24/42) of patients received IVIG supplements in the current series. About 71% of patients had at least one infectious event and the cumulative incidence of infections progressively increased with increasing duration of therapy with risk at 3, 6, 9 12, 15 months being 41%, 57%, 64%, 67% and 70%, respectively. Among these, 54% of infection were bacterial. Viral infection accounted for 41% of infections. A third of patients had new infectious events during the first 90 days following stopping bsAb treatment. 57% (8/14) of patients did not mount a response to the primary COVID19 immunization series. Among the five patients with repeat antibody titers after the booster dose, 50% were still not able to mount an antibody response. Conclusions: bsAb therapy in RRMM can be associated with profound and prolonged HGG. The cumulative risk of infection correlated with the degree of HGG and progressively increases with treatment and persisted months after being off therapy. Additionally, an impaired antibody response to the COVID-19 immunization series was also noted.

TALQUETAMAB, A G PROTEIN-COUPLED RECEPTOR FAMILY C GROUP 5 MEMBER D X CD3 BISPECIFIC ANTIBODY, IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED PHASE 1 RESULTS FROM MONUMENTAL-1

G protein-coupled receptor family C group 5 member D (GPRC5D) has limited expression in healthy human tissue but is highly expressed in malignant plasma cells, making it a promising target for immunotherapy approaches for MM. Talquetamab (JNJ-64407564) is a first-in-class bispecific antibody that binds to both GPRC5D and CD3 receptors to redirect T cells to kill MM cells. Updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) are reported (NCT03399799). Eligible patients had RRMM or were intolerant to standard therapies. Patients who were previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range: 5.0-800 μg/kg) weekly (QW) or biweekly (Q2W) with step-up dosing. The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03;cytokine release syndrome (CRS) was graded per Lee et al 2014 criteria. Responses were investigator-assessed per IMWG criteria. As of July 19, 2021, 95 patients had received SC talquetamab. The original RP2D was 405 μg/kg SC talquetamab QW with step-up doses, and a second RP2D of 800 μg/kg SC talquetamab Q2W with step-up doses was also identified. 30 patients received 405 μg/kg QW (median 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up [mF/U]: 7.5 mo [range 0.9-15.2]). 23 patients received 800 μg/kg Q2W (median 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;mF/U: 3.7 mo [range 0.0-12.0]). No treatment discontinuations due to AEs were reported at either RP2Ds. Most common AEs at the 405 μg/kg QW were CRS (73%;1 grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%). Skin-related AEs occurred in 77% of patients and were all grade 1/2 (nail disorders: 30%). Infections occurred in 37% of patients (1 grade 3 COVID-19 pneumonia). Most common AEs at 800 μg/kg Q2W were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%). Skin-related AEs occurred in 65% of patients with grade 3 events in 13% (nail disorders: 17%). Infections occurred in 13% of patients (1 grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated at 405 μg/kg QW, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR]: 57%). In 17 response-evaluable patients treated at 800 μg/ kg Q2W, the ORR was 71% (≥VGPR: 53%). Responses were durable and deepened over time with both RP2Ds (Figure). Median duration of response (DOR) was not reached at either RP2D;6-month DOR rate was 67% (95% CI: 41-84) at 405 μg/kg QW. Serum trough levels of talquetamab were comparable at both RP2Ds. Pharmacodynamic data at both RP2Ds showed peripheral T cell activation and induction of cytokines. SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data suggest that less frequent, higher doses of SC talquetamab do not negatively impact the safety profile. Further evaluation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. (Figure Presented) .

Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody.

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies have been limited by the continuous emergence of viral variants and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on the Omicron variant receptor-binding domain recognized by broadly neutralizing antibodies. Furthermore, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant receptor-binding domain as revealed by cryo-EM structures. We demonstrated that this bispecific antibody can be effectively delivered to lung via inhalation administration and exhibits exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. Importantly, this study also deciphered an uncommon and highly conserved cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

Risk of infections with BCMA-directed immunotherapy in multiple myeloma

Introduction: B cell maturation antigen (BCMA) is a novel target for T cell immunotherapy in MM including bispecific antibody (bsAb) and chimeric antigen receptor therapy (CAR-T). BCMA is critical for survival of the long-lived plasma cell, responsible for generation of protective antibodies. Impaired immune reconstitution, cytopenias, B cell aplasia and hypogammaglobinemia can compound preexisting MM-induced immunosuppression. In the case of bsAb, potential redirection/activation of T regulatory cells can create an immunosuppressive milieu. Herein, we describe the clinically relevant infectious complications observed across different BCMA-directed therapies used across multiple clinical trials at our center. Methods: Infections confirmed by microbiologic or histopathologic evidence were captured from the D1 C1 of bsAb and D 1 of lymphodepleting chemotherapy of autologous BCMA CAR-T therapies. The NCI CTCAE v5 was used to describe the site and grade of infections. Hypogammaglobinemia and severe hypogammaglobinemia were defined as ≤700 mg/dl and ≤400 mg /dl, respectively. Standard antimicrobial prophylaxis included herpes zoster prophylaxis for all MM patients with antibacterial (levofloxacin) / antifungal (fluconazole) during periods of neutropenia and IVIG supplementation as per the treating physician's discretion. PCP prophylaxis was prescribed to CAR T recipient per institutional guidelines. Descriptive statistics and comparisons were performed using two-sample t-test for continuous variables and chi-square goodness of fit test for categorical variables. Results: We identified 62 patients who received BCMA-directed bsAb (n=36) or CAR-T (n=26) between 2019-2021(table 1). The median age was 66 (range 48-84) years with % females and 14.8% of patients belonging to Black race. The median time to bsAb and CAR-T use from diagnosis were 6.6 (range 0.83-15.5) and 2.6 (range 0.35-14.4) years, respectively. The median lines of prior therapy were 6 (range 1-11) with BCMA CAR-T recipients receiving fewer prior lines of therapy (4 vs 6, p=<0.001). The baseline lymphocyte count was higher in the CAR-T (14.71 vs 0.84;p=<0.001). Baseline severe hypogammaglobulinemia and lymphopenia were present in 30% and 26.7% of all patients, respectively. Tocilizumab was used in 40.9% (bsAb -30.8% versus CAR-T 55.6%) patients for CRS. IVIG was used in 25% of patients. The median study duration for bsAb was 4 (range 0.03- 24) months across multiple dose levels. Median follow up among CAR-T recipients was 3.9 (range 0.3 - 22.3) months. Among recipients of bsAb, 41.2% of patients experienced at least one episode of infection vs. 23.1% with CAR-T (p=0.141). The cumulative incidence of infection with bsAb and CAR-T were 22 and 8, respectively. The spectrum of infections with bsAb was predominantly bacterial (64.3% While gram negative infection (Escherichia coli and Klebsiella pneumoniae bacteremia, Proteus mirabilus and Psuedomonas aeroginosa urinary tract infections) were seen in 6 patients, skin infection including cellulitis occurred in 4 patients, with 1 case of necrotizing cellulitis. Bacteremia with rare opportunistic pathogens - Rhizobium radiobacter and recurrent Ochrobacterium anthropi were also observed . Viral infections included rhinovirus, cytomegalovirus, and parvovirus B19 reactivation, and COVID-19. About 50% of infections were ≥ grade 3 with 2 grade 5 events (Pseudomonas aeruginosa bacteremia and COVID-19). In the CAR-T group, we observed more viral infections (66.7% vs 35.7%;p=0.028) and fewer bacterial infections (33.3% vs 64.3%;p=0.028) . Common viral infections included rhinovirus, RSV, and herpes simplex virus reactivation. In this group 25% of infections were ≥grade 3. Conclusion: BCMA-targeted therapies seem to be associated with clinically significant bacterial and viral infections. Repetitive dosing with bsAb therapies could be the reason for the propensity to serious bacterial infections compared to CAR-T recipients and may need novel prophylaxis strategies. (Figure Presented).

Glofitamab Plus R-CHOP Induces High Response Rates with Minimal Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results from a Dose-Escalation and Safety Run-in Phase Ib Study

Background: Over a third of pts with 1L DLBCL do not respond to, or relapse after, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP;[Sarkozy and Sehn. Ann Lymphoma 2019]). Despite recent advances, pts with R/R NHL have limited curative options. Glofitamab (Glofit) is a novel, T-cell-engaging bispecific antibody with a 2:1 molecular configuration that allows bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. Unlike other CD20xCD3 bispecific antibodies, this format uniquely enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy induces high response rates in R/R B-cell NHL (Hutchings et al. J Clin Oncol 2021). We present results of the ongoing NP40126 study (NCT03467373), designed to assess the feasibility and safety of Glofit + R-CHOP in R/R NHL (dose-escalation phase) and 1L DLBCL (safety run-in phase). Methods: R/R NHL dose-escalation: Pts (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-2) received increasing Glofit doses in separate cohorts (70µg, 1800µg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70µg and 1800µg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards). Optional Glofit maintenance was permitted (every 2 months for <2 years;dose-escalation phase only). 1L DLBCL safety run-in: Pts (ECOG PS 0-3) received Glofit 30mg plus standard R-CHOP for 6-8 cycles (each 21-day). Pts received R-CHOP in C1;Glofit step-up dosing began in C2 (2.5mg C2D8, 10mg C2D15, 30mg C3D8 and onwards). Response rates were assessed by PET-CT (Lugano criteria;[Cheson et al. J Clin Oncol 2014]). CRS events were graded by ASTCT criteria [Lee et al. Biol Blood Marrow Transplant 2019]. Results: R/R NHL dose-escalation: At data cut-off (June 10, 2021), 31 pts (23 follicular lymphoma [FL];6 transformed FL;1 marginal-zone lymphoma;1 mantle-cell lymphoma) had received Glofit with R/G-CHOP. Median age was 62 years, median prior lines of therapy was 2 (range: 1-5). In efficacy-evaluable pts (n=31), after a median 9.0 months' (range: 0-29) follow-up, the overall response rate (ORR) was 90% (n=28) and complete response rate (CRR) was 77% (n=24). Median duration of response was not reached. The Figure shows change in tumor size. Grade (Gr) ≥3 adverse events (AEs) occurred in 28 (90%) pts, serious AEs in 21 (68%) pts and CRS in 17 (55%) pts (mostly low grade;majority after the first 2.5mg Glofit dose;Table). One (3%) pt had a Gr 5 AE (COVID-19 pneumonia not related to study treatment). AEs led to Glofit dose modification/interruption in 2 (6%) pts and Glofit withdrawal in 1 (3%) pt. Neurologic AEs (NAEs) occurred in 20 (65%) pts: Gr 1-2 (16 pts, 52%);Gr 3 (4 pts, 13%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs were uncommon;a serious AE was reported in 1 pt only (Gr 3 epilepsy during the maintenance phase;resolved in 3 days). Neutropenia occurred in 24 (77%) pts. Median dose intensity was 100% for all R-CHOP components. 1L DLBCL safety run-in: At data cut-off, 13 pts were enrolled (safety population);of these, 4 pts received Glofit 30mg with R-CHOP and were efficacy-evaluable. Median age was 68 years, all pts had Ann Arbor Stage 3/4 disease. At interim assessment (C3), CRR was 100% (4/4). Of 13 pts, 1 (8%) had a CRS event (Gr 1 with fever only) after the first 2.5mg Glofit dose;no other CRS events observed. Gr ≥3 AEs occurred in 8 (62%) pts and Gr ≥3 AEs related to Glofit in 1 (8%) pt only. One (8%) pt had a serious AE and 1 (8%) pt had a Gr 5 AE (infusion-related reaction related to rituximab on C1D1). No AEs led to Glofit or R-CHOP dose interruptions. NAEs occurred in 3 (23%) pts (all Gr 1-2;none were ICANS-like). Neutropenia occurred in 6 (46%) pts. Median dose intensity was 10 % for all R-CHOP components. Conclusions: Initial data show that Glofit + R-CHOP has tolerable safety in R/R NHL and 1L DLBCL. R-CHOP dose intensity was maintained in all pts. The very low CRS rate and no neurotoxicity in 1L DLBCL may render Glofit particularly suitable for the outpatient setting without the need for hospitalization. Updated data, including end-of-treatment responses from the 1L DLBCL safety run-in phase, will be presented. [Formula presented] Disclosures: Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;AbbVie: Honoraria, Speakers Bureau;Karyopharma: Consultancy, Honoraria;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;TG Therapeutics: Consultancy, Honoraria, Research Funding;Genmab: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;Epizyme: Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria;Janssen: Consultancy, Honoraria, Speakers Bureau;Genentech: Research Funding. Townsend: Celgene (Bristol-Myers Squibb): Consultancy, Honoraria;F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Dickinson: Amgen: Honoraria;Celgene: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;Takeda: Research Funding;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau;Janssen: Consultancy, Honoraria;Bristol-Myers Squibb: Consultancy, Honoraria;Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau. Topp: Celgene: Consultancy, Research Funding;Janssen: Consultancy;Universitatklinikum Wurzburg: Current Employment;Kite, a Gilead Company: Consultancy, Research Funding;Novartis: Consultancy;Roche: Consultancy, Research Funding;Gilead: Research Funding;Regeneron: Consultancy, Research Funding;Macrogeniecs: Research Funding;Amgen: Consultancy, Research Funding. Santoro: Sandoz: Speakers Bureau;Eli-Lilly: Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AstraZeneca: Speakers Bureau;Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Speakers Bureau;Amgen: Speakers Bureau;AbbVie: Speakers Bureau;Roche: Speakers Bureau;BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda: Speakers Bureau;Sanofi: Consultancy;Arqule: Consultancy, Speakers Bureau;Novartis: Speakers Bureau;Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Crump: Novartis: Membership on an entity's Board of Directors or advisory committees;Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees;Epizyme: Research Funding;Roche: Research Funding. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech, Inc.: Consultancy;Genmab: Membership on an entity's Board of Directors or advisory committees;Roche: Consultancy, Speakers Bureau;BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Chugai: Honoraria;Incyte: Membership on an entity's Board of Directors or advisory committees;Servier: Consultancy;AstraZenenca: Membership on an entity's Board of Directors or advisory committees;Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roch Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria. Mehta: Kite/Gilead;Roche-Genetech;Celgene/BMS;Oncotartis;Innate Pharmaceuticals;Seattle Genetics;Incyte;Takeda;Fortyseven Inc/Gilead;TG Therapeutics;Merck;Juno Pharmaceuticals/BMS: Research Funding;Seattle Genetics;Incyte;TG Therapeutics: Consultancy;Seattle Genetics;Incyte;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Wu: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Barrett: Roche Products Ltd: Current Employment;F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Qayum: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Hutchings: Novartis: Research Funding;Janssen: Honoraria, Research Funding;Incyte: Research Funding;Genentech: Honoraria, Research Funding;Celgene: Research Funding;Takeda: Consultancy, Honoraria, Research Funding;Roche: Consultancy, Honoraria, Research Funding;Genmab: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Rituximab (Rituxan) is aCD20-directed cytolytic antibody indicated for the treatment of adult pts with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent;previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy;non-progressing (including stable disease), low-grade, CD20 positive, B-cell NHL as a single agent after first-line CVP chemo;previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens;previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.

Therapeutic antibodies for COVID-19: is a new age of IgM, IgA and bispecific antibodies coming?

Early humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are dominated by IgM and IgA antibodies, which greatly contribute to virus neutralization at mucosal sites. Given the essential roles of IgM and IgA in the control and elimination of SARS-CoV-2 infection, the mucosal immunity could be exploited for therapeutic and prophylactic purposes. However, almost all neutralizing antibodies that are authorized for emergency use and under clinical development are IgG antibodies, and no vaccine has been developed to boost mucosal immunity for SARS-CoV-2 infection. In addition to IgM and IgA, bispecific antibodies (bsAbs) combine specificities of two antibodies in one molecule, representing an important alternative to monoclonal antibody cocktails. Here, we summarize the latest advances in studies on IgM, IgA and bsAbs against SARS-CoV-2. The current challenges and future directions in vaccine design and antibody-based therapeutics are also discussed.

Designing of a bispecific antibody against SARS-CoV-2 spike glycoprotein targeting human entry receptors DPP4 and ACE2.

COVID-19 originated in Wuhan city, China, in 2019 erupted a global pandemic that had put down nearly 3 million lives and hampered the socio-economic conditions of all nations. Despite the available treatments, this disease is not being controlled totally and spreading swiftly. The deadly virus commences infection by hACE2 receptor and its co-receptors (DPP4) engagement with the viral spike protein in the lung alveolar epithelial cells, indicating a primary therapeutic target. The current research attempts to design an in-silico Bispecific antibody (BsAb) against viral spike glycoprotein and DPP4 receptors. Regdanvimab and Begelomab were identified to block the D614G mutated spike glycoprotein of SARS-CoV-2 and host DPP4 receptor, respectively. The designed BsAb was modified by using KIH (Knobs into Holes) and CrossMAb techniques to prevent heavy chain and light chain mispairings. Following the modifications, the site-specific molecular docking studies were performed, revealing a relatively higher binding affinity of BsAb with spike glycoprotein and DPP4 co-receptor than control BsAb. Also, for blocking the primary entry receptor, hACE2, an anti-viral peptide was linked to the Fc region of BsAb that blocks the hACE2 receptor by linker cleavage inside the infected host. Thus, the designed BsAb and anti-viral peptide therapy could be a promising triumvirate way to obstruct the viral entry by blocking the receptor engagement.

Long-term treatment with the anti CD19 antibody Tafasitamab (MOR208) in relapsed lymphoma is safe and leads to sustainable remission

Introduction: Patients with relapsed or refractory malignant lymphoma (rrNHL) after chemoimmunotherapy often do not experience longterm disease control. Therefore, novel therapeutic options are urgently needed. CD19, a type I transmembrane glycoprotein widely expressed in B-cell-lymphomas, has raised interest as a therapeutic target. Tafasitamab (formerly MOR208) is a humanized Fc-modified cytolytic CD19 antibody which exerts its efficacy via enhanced antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis, as well as direct cytotoxic effects on tumor cells. In a phase IIa study of tafasitamab in rrNHL patients and no curative option available, the antitumor activity and safety of tafasitamab was investigated. Patients received tafasitamab at a dose of 12mg/kg intravenously, weekly for 8 weeks. Treatment could be continued for additional 4 weeks when at least stable disease was reached. Patients who reached PR or CR after 12 weeks of treatment could extend their treatment until progression. Clinical outcome was promising, however the median follow-up was only 26 months and therefore, little is known about the long-term tolerability and safety of tafasitamab. Methods: We identified 5 patients from the database with rrNHL, namely FL, MZL and DLBCL, who are treated with single-agent tafasitamab for more than 5 years and performed a long-term analysis of its tolerability and safety. Only patients, for whom complete information was available concerning efficacy and toxicity and who consented for long-term evaluation of data, were selected. Results: Besides the ongoing long-term response, a very favorable safety profile was found. There were only a couple of non-severe adverse events (AEs) mostly within the first 2 years of treatment. Most common AEs were infections (45%) and neurological symptoms (14%). There were no grade 4 AEs or grade 4 late toxicities, only one episode of treatment-emergent hematological grade 3 AE and grade 3 dizziness, no late toxicities, or infusion related reactions. ECOG performance status was unimpaired. Discussion: Our data support the safety of the long-term use. Given the long-term tolerability of tafasitamab, it can be considered as a safe agent in combination with chemotherapy, kinase inhibitors, bispecific antibodies, EZH2-inhibitors, or other options. In a future project, we will analyse the response to Covid-19 vaccination in these patients.

Updated Phase 1 Results from MonumenTAL-1: First-in-Human Study of Talquetamab, a G Protein-Coupled Receptor Family C Group 5 Member D x CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Introduction: Despite recent advances in treatment, patients with multiple myeloma (MM) continue to relapse. G protein-coupled receptor family C group 5 member D (GPRC5D) is a promising target for immunotherapy in patients with MM due to its high expression in malignant plasma cells and limited expression in normal human tissue;unlike other antigens targeted by MM therapies, there is no indication that GPRC5D sheds into the periphery. Talquetamab (JNJ-64407564) is a first-in-class bispecific IgG4 antibody that redirects T cells to kill MM cells by binding to both GPRC5D and CD3 receptors. Here we report updated and new results of talquetamab at the recommended phase 2 doses (RP2Ds) from a phase 1 trial in relapsed/refractory MM (RRMM;NCT03399799). Methods: Eligible patients with MM had relapsed or refractory disease or were intolerant to standard therapies;patients previously treated with B-cell maturation antigen (BCMA)-directed therapies were eligible. This analysis focuses on patients who received talquetamab subcutaneously (SC;range 5.0-800 µg/kg) weekly or biweekly. Step-up dosing was used as a patient management strategy to minimize the severity of cytokine release syndrome (CRS). The primary objectives were to identify the RP2D (part 1) and assess talquetamab safety and tolerability at the RP2Ds (part 2). Adverse events (AEs) were graded by CTCAE v4.03 with CRS events graded per Lee et al 2014 criteria. Responses were investigator-assessed per International Myeloma Working Group criteria. Results: As of July 19, 2021, 95 patients have received SC talquetamab. The RP2D was originally identified as a weekly SC dose of 405 µg/kg talquetamab with step-up doses. However, alternative dosing schedules that require less frequent administration continue to be investigated. A biweekly RP2D was also identified as an SC dose of 800 µg/kg talquetamab with step-up doses. 30 patients received the 405 µg/kg weekly dosing schedule (median age: 61.5 years [range 46-80];63% male;100% triple-class exposed;80% penta-drug exposed;77% triple-class refractory, 20% penta-drug refractory;30% prior BCMA-directed therapy;median follow-up: 7.5 mo [range 0.9-15.2]). 23 patients received the 800 µg/kg biweekly dosing schedule (median age: 60.0 years [range 47-84];48% male;96% triple-class exposed;70% penta-drug exposed;65% triple-class refractory, 22% penta-drug refractory;17% prior BCMA-directed therapy;median follow-up 3.7 mo [range 0.0-12.0]). There were no treatment discontinuations due to AEs at either of the RP2Ds. The most common AEs at the 405 µg/kg weekly dose were CRS (73%;1 patient had grade 3 CRS), neutropenia (67%;grade 3/4: 60%), and dysgeusia (60%;grade 2: 29%);skin-related AEs occurred in 77% (all grade 1/2;nail disorders: 30%) of patients, and infections occurred in 37% of patients (1 patient had grade 3 COVID-19 pneumonia). The most common AEs at the 800 µg/kg biweekly dose were CRS (78%;all grade 1/2), dry mouth (44%;all grade 1/2), and neutropenia (44%;grade 3/4: 35%);skin-related AEs occurred in 65% of patients (grade 3: 13%;nail disorders: 17%) and infections occurred in 13% of patients (1 patient had grade 3 pneumococcal sepsis). In 30 response-evaluable patients treated with the 405 µg/kg weekly dose, the overall response rate (ORR) was 70% (very good partial response or better [≥VGPR] rate: 57%). In 17 response-evaluable patients treated with the 800 µg/kg biweekly dose, the ORR was 71% (≥VGPR rate: 53%). Responses were durable and deepened over time in both cohorts (Figure). Median duration of response (DOR) was not reached at either RP2D;the 6-month DOR rate for patients who received the 405 µg/kg weekly dose was 67% [95% CI: 41-84]. Serum trough levels of talquetamab were comparable at both RP2Ds. Consistent with the mechanism of action for talquetamab, pharmacodynamic data from cohorts treated at both dose levels showed peripheral T-cell activation and induction of cytokines. Conclusions: These findings indicate that SC talquetamab is well tolerated and highly effective at both RP2Ds. Preliminary data from the 800 µg/kg biweekly cohorts indicate that less frequent, higher doses of SC talquetamab do not have a negative impact on the previously described safety profile. Further investigation of talquetamab as monotherapy (phase 2;NCT04634552) and in combination with other therapies in patients with RRMM is underway. [Formula presented] Disclosures: Krishnan: MAGENTA: Consultancy;BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau;JANSSEN: Consultancy, Research Funding;City of Hope Cancer Center: Current Employment;REGENERON: Consultancy;SANOFI: Consultancy;GSK: Consultancy;Amgen: Speakers Bureau. Minnema: Celgene: Other: Travel expenses;Alnylam: Consultancy;Cilag: Consultancy;BMS: Consultancy;Janssen: Consultancy;Kite/Gilead: Consultancy. Berdeja: Lilly, Novartis: Research Funding;Abbvie, Acetylon, Amgen: Research Funding;Celularity, CRISPR Therapeutics: Research Funding;EMD Sorono, Genentech: Research Funding;Poseida, Sanofi, Teva: Research Funding;Bluebird bio, BMS, Celgene, CRISPR Therapeutics, Janssen, Kite Pharma, Legend Biotech, SecuraBio, Takeda: Consultancy;GSK, Ichnos Sciences, Incyte: Research Funding. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk: Roche: Consultancy;Takeda: Consultancy;Cellectis: Research Funding;Amgen: Consultancy, Research Funding;Janssen: Consultancy, Research Funding;BMS/Celgene: Consultancy, Honoraria;Novartis /bayer/servier: Consultancy. Rodriguez-Otero: Clínica Universidad de Navarra: Current Employment;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Consultancy;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria;Regeneron: Honoraria. Askari: Janssen: Research Funding. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Honoraria;Bluebird bio: Honoraria;AbbVie: Honoraria;GSK: Honoraria;Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Costa: BMS: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding;Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria, Speakers Burea . Verona: Janssen: Current Employment. Ma: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Girgis: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Yang: Janssen: Current Employment. Hilder: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Russell: Janssen: Ended employment in the past 24 months. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Chari: Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees;Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding;Millenium/Takeda: Consultancy, Research Funding;Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Research Funding;Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Pharmacyclics: Research Funding;Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees;GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Research Funding;Genentech: Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.