Review Article
Bispecific antibodies for the treatment of B-cell
lymphoma: promises, unknowns, and opportunities
Lorenzo Falchi, Santosha A. Vardhana, and Gilles A. Salles
Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Treatment paradigms for B-cell non-Hodgkin lymphomas
(B-NHL) have shifted dramatically in the last 2 decades
following the introduction of highly active immunother-
apies such as rituximab. Since then, the field has
continued to witness tremendous progress with the
introduction of newer, more potent immunotherapeu-
tics, including chimeric antigen receptor T-cell therapy,
which have received regulatory approval for and
currently play a significant role in the treatment of these
diseases. Bispecific antibodies (BsAb) are a novel class of
off-the-shelf T-cell redirecting drugs and are among the
most promising immunotherapeutics for lymphoma
today. BsAb may target various cell-surface antigens and
Introduction
B-cell non-Hodgkin lymphomas (B-NHL) are a heterogeneous
group of neoplasms that are curable or highly treatable with
conventional cytotoxic polychemotherapy. Treatment para-
digms for these diseases have been profoundly reshaped over
the years by the introduction of highly active immunotherapies
that work in concert with the host immune system. The anti-
CD20 monoclonal antibody rituximab, which significantly
improved the chance of cure for patients with aggressive lym-
phoma1 and markedly increased the overall survival (OS) of
those diagnosed with indolent lymphoma,2 works primarily
through Fc-gamma receptor (FcγR)–mediated mobilization of
cytotoxic and phagocytic host immune cells.3 More recently,
autologous chimeric antigen receptor (CAR) T-cell therapy
using genetically engineered T cells redirected against
lymphoma-associated antigens, such as CD19, demonstrated
significant clinical efficacy, emphasizing how non–major
histocompatibility complex (MHC)–restricted T-cell receptor–
mediated T-cell activation can induce potent antitumor activ-
ity. Prolonged responses in patients whose lymphoma was
refractory to standard chemotherapy led to positioning autol-
ogous CAR T-cell therapy as an accepted standard of care in
several clinical settings.4-10 However, broad adoption of this
treatment strategy is limited by a combination of manufacturing
delays and treatment-related toxicities. More recently, off-the-
shelf bispecific antibodies (BsAb), which activate peripheral
and intratumoral endogenous immune cells by cotargeting
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exist in different formats. Anti-CD20xCD3 BsAb have
demonstrated remarkable single-agent activity in
patients with heavily pretreated B-NHL with a manage-
able toxicity profile dominated by T-cell overactivation
syndromes. Much work remains to be done to define the
optimal setting in which to deploy these drugs for B-NHL
treatment, their ideal combination partners, strategies
to minimize toxicity, and, perhaps most importantly,
pharmacodynamic biomarkers of response and resis-
tance. In this review, we provide an update on BsAb
development in B-NHL, from discovery to clinical appli-
cations, highlighting the achievements, limitations, and
future directions of the field.
tumor antigens and T- or natural killer cells in an FcγR- and
MHC-independent manner, have begun to emerge. Although
the scope of their clinical development has been broad in
hematological and solid tumors, these products have proven
especially active in patients with B-NHL and may represent the
next therapeutic milestone in these diseases.
Preclinical development
Structural properties
Bispecific products can be divided into those that possess a
fragment crystallizable (Fc), and thus an immunoglobulin (Ig)–
like structure, and those that do not. Various manufacturing
technologies have been used for BsAb synthesis, each resulting
in constructs with unique structural and pharmacologic prop-
erties. A systematic review of all BsAb formats is offered else-
where.11 Here, we will concentrate on the characteristics of
T-cell–engaging BsAb currently in clinical development for the
treatment of B-NHL.
BsAb can be distinguished by the way in which moieties of
different specificity are assembled. Because BsAb result from
different combinations of heavy and light chain variable
domains, random assembly of the heavy chains and/or mis-
matched coupling of heavy and light chains can compromise
the purity of the final product and, therefore, its bispecificity.
One way to overcome this problem is to generate individual
antigen-binding fragments (scFv) and fuse them either
2 FEBRUARY 2023 | VOLUME 141, NUMBER 5 467
chemically or through physical linkage, as is the case for bis-
pecific T-cell engagers or dual affinity redirecting antibodies.11
Most BsAb in development for B-NHL, however, have a full-
length, IgG-like structure, which shares the pharmacologic
properties of monoclonal antibodies (Table 1). The first and
best-characterized approach to manufacturing IgG-like BsAb
has been the “knobs-into-holes” technology,12 where comple-
mentary mutations are introduced in the CH3 domain of each
antibody moiety, thus allowing for consistent pairing of heavy
chains. In another platform, “knobs-into-holes” or similar tech-
nology is used to allow heavy chains to heterodimerize, and
light chain mispairing is overcome by crossover of the anti-
body’s entire Fab domain, variable domain, or constant domain
within 1 Fab-arm of the BsAb.13,14 With this technology, biva-
lent (1:1), trivalent (2:1), or tetravalent (2:2) antibodies can be
generated that retain the antigen-binding capacity of the
parental antibody while displaying variable avidity for the target
epitope and distinct cytotoxic potential.15 A variety of other
technologies have been used to manufacture Ig-like BsAb,
including controlled Fab-arm exchange, where a library of BsAb
is first generated and then the best candidate is chosen based
on its ability to bind both epitopes and induce cytotoxicity,16 as
well as the creation of an IgG4-based heterodimer with
different heavy chains but a common light chain.17
Other elements of differentiation among BsAb include number,
distribution, and specificity of the Fab arms. CD20xCD3 BsAb
may possess 112,16,18 or more CD20-binding Fabs13,14,19 and, as
a consequence, different target-binding avidity and ability to
elicit effector functions. For instance, in vitro, a CD20xCD3
BsAb with 2 CD20-binding sites (2:1 format) induced 40-fold
greater tumor lysis than its 1:1 BsAb counterpart.15 Interest-
ingly, a BsAb with CD20- and CD3-binding sites arranged in a
head-to-tail fashion on the same Fab had greater potency than
the variant with 1 binding site on each Fab.15 Overall, these 2
modifications resulted in increased binding avidity and stabili-
zation of the tumor-T-cell synapse, indicating that BsAb-
mediated tumor in vitro killing is in part influenced by the
spatial configuration of the 2 binding moieties. Furthermore,
distinct BsAb recognize different epitopes on the CD20 antigen
(Table 1), which may have important implications for combina-
torial strategies (see below). Finally, multispecific antibodies
with 2:1 or 2:2 formats recognizing 2 distinct antigens on tumor
cells (advantageous for tumors with antigen low-density or
potential loss) or targeting CD3 and a T cell costimulatory
antigen are being developed in different disease contexts.
A structural feature shared among most Ig-like BsAb is the
presence of mutations in their Fc domain. These are designed
to prevent antibody-dependent FcγR-mediated crossbinding of
CD3 and T cells, which could result in antigen-independent T-
cell activation and cytotoxicity, as well as fratricidal antibody-
dependent cellular cytotoxicity and complement-dependent
cytotoxicity. In contrast, the neonatal FcR binding is usually
preserved to prolong the drug half-life in vivo.12,16,18
Pharmacodynamics (PD)
A crucial step in developing effective BsAb is careful target
selection. CD19 and CD2020 are relatively stable cell-surface
antigens widely expressed on B cells and have been used as
targets for most BsAb currently in development for B-NHL. In 1
468 2 FEBRUARY 2023 | VOLUME 141, NUMBER 5
experiment, BsAb cotargeting CD3 and other B-cell antigens
(eg, CD22, CD37, CD70, CD79b, CD138, or HLA-DR) induced
lower cytotoxicity compared with those cotargeting CD3 and
CD20, even when the expression levels of these B-cell antigens
were comparable.16 Other factors that can influence tumor cell
killing are antigen-binding affinity, molecular size, flexibility,
mobility, localization of the epitope on the cell surface, BsAb
format, ease of immunological synapse formation, balance
between costimulatory and coinhibitory molecules influencing
T-cell activation, and the residual or concomitant presence of
other competing therapeutic antibodies that could result in
steric hindrance.
All BsAb work by simultaneously binding target tumor cells and
immune effector cells (eg, T-cells, macrophages, or natural killer
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cells), which become activated and cause tumor cell killing. In
the case of T-cell engagers, cytotoxicity occurs in a MHC-
independent fashion, thus bypassing the restrictions imposed
by the MHC-T-cell receptor interaction.11 This feature is criti-
cally important as many B-NHL, in particular diffuse large B-cell
lymphoma (DLBCL), frequently exhibit genetic aberrations that
abolish expression of MHC class I molecules.21,22 Affinity for T-
cell binding (often via CD3) is equally important, as it affects the
ability of the T cell to form a functional immune synapse and be
optimally activated. Of note, BsAb against CD3, a marker
expressed on all T-cell subpopulations, are likely to engage
effector and noneffector T cells alike, and the net functional
effects of indiscriminate T-cell activation are presently unknown.
antibody-dependent cellular cytotoxicity and complement-
dependent cytotoxicity are not expected to contribute to
BsAb-mediated cell cytotoxicity due to the aforementioned
mutations introduced in the Fc domain of most products.
CD19-directed BsAb
Blinatumomab is a CD19xCD3 bispecific T-cell engager
comprised of 2 single-chain antibody fragments, respectively
against CD19 and against CD3, connected by a linker.23 At
femtomolar concentrations, blinatumomab simultaneously
bound CD3 and CD19, increased T-cell motility, activation, and
proliferation, and produced rapid, serial CD19+ malignant
B-cell lysis in coculture experiments.24 Duvortuxizumab is an
example of a CD19xCD3 dual affinity redirecting antibody in
which the variable heavy chain domain of the first moiety is
linked to the variable light chain domain of the second and vice
versa. In a Burkitt’s lymphoma mouse model, duvortuxizumab
induced CD4+ and CD8+ T-cell tumor infiltration, activation,
effector memory (CD45RA− CCR7−) differentiation, and
cytotoxicity.25
CD20-directed IgG BsAb
Mosunetuzumab, the first-in-class CD20xCD3 IgG-like BsAb,
underwent extensive preclinical development. Experiments
conducted in vitro and on mice engineered to express human
CD20 and CD3ε revealed that the drug was active at very low
concentrations and exerted cytotoxicity primarily through acti-
vated CD69+CD8+ T cells. Tumor killing peaked at 24 hours
and decreased around day 3, when B cells had been mostly
cleared, supporting the notion that mosunetuzumab-mediated
T-cell activation occurs conditionally upon B-cell binding.
Furthermore, mosunetuzumab retained its activity in combina-
tion with an effectorless variant of rituximab (which contributes
FALCHI et al
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Table 1. Comparative characteristics of CD20XCD3 BsAb currently in development

Schematic CD20:CD3
Product name depiction Format Technology ratio CD3 clone CD20 clone Fc silencing mutations*
Mosunetuzumab18 IgG1 Knobs-into-holes 1:1 UCHT1v9 (CD3δε) 2H7 (type 1 epitope, identical to N297G (no FcγR binding)
(different Fabs) rituximab)

Glofitamab15 IgG1 Head-to-tail fusion 2:1 SP34-der.(CD3ε) By-L1 (type 2 epitope, identical to IgG1-P329G-LALA (no FcγR
obinutuzumab) binding)

Epcoritamab16 IgG1 Controlled Fab-arm 1:1 huCACAO (SP34- 7D8 (type 1 epitope, shared by L234F,L235E,D265A (no
exchange der.)(CD3ε) ofatumomab) FcγR,C1q binding)

Odronexamab17 IgG4 Heavy chains with 1:1 REG1250 (CD3δε) 3B9-10 (type 1 epitope, shared by Modified IgG4 (no FcγRIII
different affinity ofatumomab) binding)

Plamotamab90 IgG1 Fab-Fc x scFv-Fc 1:1 α-CD3_H1.30 (SP34- C2B8_H1_L1 (type 1 epitope, shared G236R, L328R (no FcγR
der.)(CD3ε) by rituximab) binding)
2 FEBRUARY 2023 | VOLUME 141, NUMBER 5 469

IgM 232319 IgM IgM + modified J chain 10:1 Not reported Not reported No

*These Fc-silencing mutations do not abolish the binding of BsAb to neonatal FcR.
to CD20 occupancy but not to cytotoxic activity), suggesting
that coadministration of the 2 drugs may be feasible.18
The preclinical development of a second BsAb, glofitamab,
stemmed from the observation that directly fusing a CD20 Fab
and a CD3 Fab “head-to-tail”14 may elicit superior biological
activity than placing a CD3 Fab and a CD20 Fab on each
antibody arm. Indeed, incubation of tumor B cells with glofita-
mab resulted in tumor-T-cell synapse formation and marked
tumor lysis as early as 4 hours following tumor encounter. In
humanized nonobese diabetic/severe combined immunodefi-
ciency gamma mice, weekly glofitamab resulted in peripheral
and tissue B-cell clearance within 24 hours of the first full dose
(0.5 mg/kg), and those remained undetectable throughout the
experiment.15
The preclinical development of epcoritamab contributed addi-
tional insights into the BsAb mechanism of action. In vitro,
epcoritamab induced dose-dependent activation of CD4+ and
CD8+ T cells, release of perforin, and CD8+ T-cell–mediated
reversible B-cell depletion when coincubated with various
CD20+ B-NHL cell lines, regardless of CD20 expression level. In
addition, both intravenous (IV) and subcutaneous (SC) epcor-
itamab suppressed the growth of CD20+ lymphoma xenografts
in nonobese diabetic/severe combined immunodeficiency mice
with a humanized immune system. An Fc-silenced rituximab
variant coadministered in doses up to 10 mg/kg did not reduce
epcoritamab’s cytotoxic potential.16
Clinical pharmacology
Unlike blinatumomab, which is a small molecule characterized
by rapid clearance and a short half-life, thus requiring contin-
uous infusion,26 full-length BsAb share pharmacokinetic (PK)
characteristics with monoclonal antibodies and endogenous
IgG and can therefore be dosed at longer intervals. In preclin-
ical PK/PD studies, these agents exhibited at first nonlinear,
time-varying PK due to initial rapid target-mediated clearance
followed by a linear, more predictable clearance, allowing IV
dosing every 1 to 4 weeks.27 In phase 1 trials, most BsAb
administered IV showed a dose-dependent Cmax and a half-life
of 6 to 14 days that was shorter than the typical 21-day half-life
of most IgG, likely owing to the initial target-mediated drug
clearance.17,28-30 Compared with the IV formulation, SC dosing
was associated with slower absorption and a lower Cmax, but a
similar area under the curve with both delayed and lower peak
levels of inflammatory cytokines.30-32
Given the unique properties and mechanism of action of BsAb,
novel integrated PK/PD models have been devised to identify
optimally biologically effective (rather than maximum tolerated)
doses by correlating drug exposure, changes in the B- and
T-cell dynamics in different body compartments, and clinical
response. These models demonstrated consistent PD effects
with limited interindividual viariability using flat dosing, sug-
gesting that weight- or body surface area–based BsAb dosing is
likely unnecessary.33-36 In phase 1 trials, the dose-response
relationship usually followed a sinusoidal pattern, with no
meaningful clinical activity seen until a dose threshold, then a
linear correlation between dose and response, and finally a
plateau, beyond which larger doses did not produce incre-
mentally higher response rates.28-30,36 The formation of
470 2 FEBRUARY 2023 | VOLUME 141, NUMBER 5
antibodies directed against the BsAb has not been reported so
far in patients.
Current clinical results in B-cell
lymphoma
Blinatumomab was the first BsAb to enter the clinical arena. In a
phase 1 trial in selected patients with relapsed or refractory
(R/R) B-NHL, it produced encouraging response rates with
durable benefit.26 Subsequent experiences in heavily pre-
treated individuals with DLBCL confirmed high efficacy, with an
overall response rate (ORR) just above 40% and ~20% complete
responses (CR), a small number of which were durable.37-39 The
cumbersome dosing schedule and significant neurological
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toxicities observed in these studies somewhat limited blinatu-
momab’s prospects for further clinical development. In contrast,
the more favorable efficacy and safety profiles seen so far with
CD20xCD3 IgG-like BsAb have hastened their development in
patients with diverse R/R B-NHL (Table 2).
Single-agent clinical efficacy
Mosunetuzumab was evaluated in patients with R/R B-NHL in
several phase 1 and 2 studies. In the first,28 mosunetuzumab
was administered IV every 3 weeks for up to 8 cycles in patients
who achieved a CR and up to 17 cycles in those who achieved a
lesser response. Among 197 subjects, 43 were treated at a
target dose of 13.5 mg, and 154 at 30 mg. About one-third of
the patients had follicular lymphoma (FL), whereas the remain-
ing had aggressive B-NHL (aNHL). The median number of prior
therapies was 3, and 10% had previously received CAR T-cell
therapy. Excluding the single-patient dose-escalation cohorts,
the ORR, CR rate, and median duration of response (DOR) in
patients with aNHL were 35%, 19%, and 7.6 months, respec-
tively, with a median progression-free survival (PFS) of 1.4
months, whereas in those with indolent (i) NHL, these figures
were 66%, 48%, 16.8 months, and 11.8 months, respectively.
Responses were consistent across risk groups, including
patients previously exposed to CAR T-cell therapy,28 and similar
patients treated with IV or SC formulations.31 An analysis of 90
subjects with R/R FL treated in this study at the target dose of
30 mg was recently published.40 At an extended follow-up of
18.3 months, the best ORR was 80% and the CR rate was 60%.
Responses were noted across demographic and risk groups,
including patients older than 65 years,41 those refractory to anti-
CD20 antibodies and alkylating agents, and those with early
progression following first-line therapy.42 The median DOR and
PFS were 22.8 months and 17.9 months, respectively, and the
estimated 18-month OS rate was 90%.43 These data led to the
approval of mosunetuzumab for patients with R/R FL after ≥2
prior lines of therapy by the European Medicines Agency.44
A report of the first 2 portions (dose escalation and dose
expansion) of a 3-part international phase 1 study of glofitamab
included 171 adults with CD20-positive B-NHL previously
exposed to a median of 3 prior lines of therapy.29 Patients
received a single 1000 mg dose of pretreatment obinutuzumab
followed by fixed or step-up dosing IV glofitamab every 2 or 3
weeks. The drug exhibited dose-dependent clinical activity
starting at 0.6 mg, and at doses ≥10 mg the ORR among
patients with aNHL was 61%, including 49% CR. Similarly
encouraging results were observed in 44 patients with grade
FALCHI et al
 BISPECIFIC ANTIBODIES IN THE TREATMENT OF LYMPHOMA

Table 2. Conceptual overview of BsAb studies with available results

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Median N.
Median prior % Prior
Report age, y therapies ASCT/prior ORR Follow-up
Disease Setting Modifiers Trial ID format Phase Drug(s) Histology N. (range) (range) CAR-T (CR), % DOR, mo PFS, mo (mo)
aNHL* First line R-CHOP NCT03677141 Abs I/II MOSUN- DLBCL 40 65 (39-79) 0 NA 82 (79) NR NR NR
candidate CHOP
NCT03467373 Abs I GLOFIT-R- DLBCL 26 68 (26-84) 0 NA 100 (89) NR NR NR
CHOP
NCT04663347 Abs I/II EPCOR-R- DLBCL 24 65 (30-82) 0 NA 100 (73) nr (1-6.5+) NR 1.3 (0.2-7.9)
CHOP
Older/unfit NCT03677154 Abs I/II MOSUN (IV) DLBCL 29 82 (67-100) 0 NA 63 (45) nr (0.2-13+) NR 5.4 (0.3–16.2)
≥second Transplant NCT04663347 Abs I/II EPCOR-R- DLBCL 29 58 (28-75) 1 (1-3) 0/10 100 (86) NR NR 5.8 (1.5-11.4)
line eligible DHAX
Transplant NCT04663347 Abs I/II EPCOR- DLBCL 26 71 (47-87) 2 (1-13) 12/12 92 (60) NR NR 9 (1-15)
ineligible GemOx
NCT02500407 Paper I/II MOSUN (IV) Multiple 116 63 (19-91) 3 (1-14) 34/12 35 (19) 7.6 (5.6-2.8) 1.4 (1.4-2.9) NR
NCT02500407 Abs I/II MOSUN Multiple 50 68 (41-88)† 3.5 (1-9)† 17/42† 29 (18) NR NR 4.2 (0.1-7.8)†
(SC)
NCT03075696 Abs I/II GLOFIT Multiple 155 66 (21-90) 3 (2-7) 18/33 52 (39) 18.4 (13.7-NE) 4.9 (3.4-8.1) 12.6 (0-22)
NCT03625037 Paper I/II EPCOR Multiple 157 64 (20-83) 3 (2-11) 20/39 63 (39) 12 (0+-15.5+) 4.4 (3.0-7.9) NR
NCT04082936 Abs I IgM2323 DLBCL 18 64 (36-84)† 3 (2-9)† 8/20† 31 (25) nr (2-1.5+)† NR 7.8 (0.4-23.7)†
NCT02924402 Abs I PLAMO Multiple 46 61.5 (31-82)† 4 (1-10)† 13/NR† 51 (25)† NR NR NR
NCT02290951 Paper I ODRON Multiple 85 67 (57-73)† 3 (2-5)† 8/29† 37 (24) 4.4 (2.9-NE); nr 2 (0.9-5.3)‡ 4.2 (1.5-11.5)†
(1.6-NE)‡
NCT03671018 Abs I/II MOSUN- DLBCL 60 68 (20-83) 3 (1-8) NR/40 65 (48) nr (6.3 - NE) 8.9 (3.5-NE) 5.7 (0.7-27.5)
pola
NCT03533283 Abs I/II GLOFIT- Multiple 59 59 (29-82) 2 (1-5) NR/NR 80 (51) nr (0.5-23+) NR 3.7 (1.9-5.3)
2 FEBRUARY 2023 | VOLUME 141, NUMBER 5 471

pola

Reported abstract data refer to the time of their presentation; Only studies with ≥10 evaluable patients are listed; DLBCL includes DLBCL, not otherwise specified, high-grade B-cell lymphoma, and transformed indolent NHL.
ASCT, high-dose therapy and autologous stem cell support; B-NHL, B-cell non-Hodgkin lymphoma; BTKi, Bruton tyrosine kinase inhibitors; CAR-T, chimeric antigen receptor T-cell therapy; CR, complete response; DHAX, dexamethasone, cytarabine,
oxaliplatin; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; EPCOR, epcoritamab; FL, follicular lymphoma; GemOx, gemcitabine, oxaliplatin; GLOFIT, glofitamab; len, lenalidomide; MCL, mantle cell lymphoma; MOSUN, mosunetuzumab;
obin, obinutuzumab; MZL, marginal zone lymphoma; NA, not applicable; NE, not estimable; NR, not reported; nr, not reached; ODRON, odronextamab; ORR, overall response rate; PFS, progression-free survival; PLAMO, plamotamab; pola, polatuzumab, R-
CHOP, rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone; SC, subcutaneous.
*Most studies excluded Richter syndrome and Burkitt lymphoma.
†Refers to the entire study population.
‡Refers to patients with and without previous CAR T-cell therapy, respectively.
§Most studies excluded chronic lymphocytic leukemia and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
‖Partially overlapping populations.
¶Refers to patients with FL only.
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Table 2 (continued)

Median N.
Median prior % Prior
Report age, y therapies ASCT/prior ORR Follow-up
Disease Setting Modifiers Trial ID format Phase Drug(s) Histology N. (range) (range) CAR-T (CR), % DOR, mo PFS, mo (mo)
Indolent B- ≥second After anti-CD20 NCT02500407 Paper I/II MOSUN (IV) Multiple 68‖ 60.5 (27-85) 3 (1-11) 18/6 66 (48) 16.8 (11.7-NE) 11.8 (8.4-NE) NR
NHL§ line and
NCT02500407 Paper I/II MOSUN (IV) FL 90‖ 60 (29-90) 3 (2-4) 21/3 80 (60) 22.8 (9.7-NE) 17.9 (10.1-NE) 18.3 (2-27.5)
alkylating
agents NCT02500407 Abs I/II MOSUN FL 12 68 (41-88)† 3.5 (1-9)† 17/42† 82 (64) NR NR 4.2 (0.1-7.8)†
(SC)
NCT03075696 Abs I/II GLOFIT FL 75 64 (22-86)† 3 (1-13)† 12/5† 81 (69) NR NR NR
NCT03075696 Abs I/II GLOFIT- FL 19 61 (41-78) 2 (1-5) 16/0 100 (74) NR NR 5.5 (5.4-6.3)
obin
NCT03625037 Paper I/II EPCOR FL 12 73 (63-76) 4.5 (2.5-8) 8/0 90 (50) 6 (2.5-15.5) NR 13.6 (10.4-16.5)
NCT04082936 Abs I IgM2323 FL, MZL 18 64 (36-84)† 3 (2-9)† 8/20† 28 (22) nr (2-21.5+)† NR 7.8 (0.4-23.7)†
NCT02924402 Abs I PLAMO Multiple 17 61.5 (31-82)† 4 (1-10)† 13/NR† 51 (25)† NR NR NR
NCT02290951 Paper I ODRON FL, MZL 46 67 (57-37)† 3 (2-5)† 8/29† 76 (59)¶ MZL: 18.1 (1.5-NE) MZL: NR 4.2 (1.5-11.5)†
NCT03467373 Abs I GLOFIT-R- FL, MZL (tFL) 31 62 (34-78) 2 (1-5) NR/NR 90 (81) NR NR 9 (0-29)
CHOP
NCT04246086 Abs I MOSUN FL 29 59 (30-79) 1 (1-6) NR/NR 90 (65) nr (0.3-12.3+) NR 5.4 (3-12)
(IV)-len
NCT04663347 Abs I/II EPCOR-R- FL 29 67 (42-80) 1 (1-5) 17/NR 100 (92.3) nr (0.3-6.5+) NR NR
len

MCL ≥third line post-BTKi NCT03075696 Abs I/II GLOFIT MCL 29 69 (41-84) 3 (1-6) NR/NR 81 (67) NR (1-28.5+) NR 1.4 (CI NR)
NCT02290951 Paper I ODRON MCL 12 67 (57-37)† 3 (2-5)† 8/29† 50 (33) 10.9 (1.4-NE) NR 4.2 (1.5-11.5)

Reported abstract data refer to the time of their presentation; Only studies with ≥10 evaluable patients are listed; DLBCL includes DLBCL, not otherwise specified, high-grade B-cell lymphoma, and transformed indolent NHL.
ASCT, high-dose therapy and autologous stem cell support; B-NHL, B-cell non-Hodgkin lymphoma; BTKi, Bruton tyrosine kinase inhibitors; CAR-T, chimeric antigen receptor T-cell therapy; CR, complete response; DHAX, dexamethasone, cytarabine,
oxaliplatin; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; EPCOR, epcoritamab; FL, follicular lymphoma; GemOx, gemcitabine, oxaliplatin; GLOFIT, glofitamab; len, lenalidomide; MCL, mantle cell lymphoma; MOSUN, mosunetuzumab;
obin, obinutuzumab; MZL, marginal zone lymphoma; NA, not applicable; NE, not estimable; NR, not reported; nr, not reached; ODRON, odronextamab; ORR, overall response rate; PFS, progression-free survival; PLAMO, plamotamab; pola, polatuzumab, R-
CHOP, rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone; SC, subcutaneous.
*Most studies excluded Richter syndrome and Burkitt lymphoma.
†Refers to the entire study population.
‡Refers to patients with and without previous CAR T-cell therapy, respectively.
§Most studies excluded chronic lymphocytic leukemia and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
‖Partially overlapping populations.
¶Refers to patients with FL only.
FALCHI et al
1-3A FL, with an ORR of 70% and a 48% CR rate. Most
responses were observed after the first 6 weeks of therapy, and,
despite the short observation time (2.9 months), the median
duration of CR was not reached, with no relapses seen in
complete responders 8 months from study entry.29 In a recent
analysis of 155 patients with aNHL treated with glofitamab at
the recommended phase 2 target dose of 30 mg, the ORR and
CR rates were 52% and 39%, respectively, with similar rates of
CR observed in the 52 subjects previously exposed to CAR T-
cell therapy (35%) and in the 102 who were not (42%).45 At a
median follow-up of 12.6 months, the median DOR was 18.4
months, the PFS was 4.9 months, and the OS was 11.5
months.46 In a separate analysis of patients with R/R FL treated
with step-up dosing glofitamab with (N = 19) or without (N = 21)
concomitant obinutuzumab, similar deep tumor volume
reductions were observed regardless of obinutuzumab admin-
istration.47 Finally, in a preliminary report on 21 patients with R/
R mantle cell lymphoma, an 81% ORR with 67% CR were
observed with glofitamab, regardless of prior Bruton tyrosine
kinase inhibitor therapy.48
Epcoritamab was tested in a phase 1/2 trial in 73 subjects with
R/R B-NHL at doses ranging from 0.0128 to 60 mg.30 Treatment
was given SC initially weekly, then every 2 weeks, then every 28
days. Among 22 patients with aNHL treated at doses between
12 mg (the minimum clinically active dose) and 60 mg, the ORR
was 68% and the CR rate was 45%, and the median time to first
and to CR were 1.4 and 2.7 months, respectively. At a median
follow-up of 9.2 months, 75% of responding patients had
remained relapse-free for at least 6 months. In the same phase
1/2 study, 9 of the 10 patients with R/R FL achieved a response,
including 5 CR, and activity was seen in a small cohort of
patients with mantle cell lymphoma.30 More recently, data from
the phase 2 study cohort in subjects with R/R aNHL were
reported. Among 157 patients, 61 of whom with prior CAR T-
cell therapy, the ORR and CR rates were 63% and 39%
respectively, with similar response rates observed in CAR-T–
naïve (ORR, 69%; CR, 42%) and CAR-T–exposed (ORR, 54%;
CR, 34%) individuals. At the 12-month mark, 80% of CRs were
maintained, and 67% of patients were alive.49 A phase 3 trial of
epcoritamab vs physician’s choice in patients with R/R DLBCL
ineligible for curative therapy is underway.
Odronextamab was tested in a phase 1 trial in 145 patients with
R/R B-NHL at doses from 0.1 to 320 mg weekly for 9 weeks,
then every other week until progression. The median number of
prior therapies was 3, and 41% of the 85 patients with DLBCL
had previously received CAR T-cell therapy. Clinical activity was
seen at doses ≥80 mg in patients with DLBCL and ≥5 mg in
those with FL. In patients with DLBCL, responses were similar
for those who had received CAR T-cell therapy and those who
had not (ORR 33% and 39%, respectively; CR rate 24% in both
groups). Among patients with FL, 78% had an objective
response and 63% had a CR.36
Preliminary clinical data are also available for the pentameric
CD20xCD3 BsAb IgM-2323 (N = 40), with objective responses
seen in a third of patients and CR in 20%,50 and for plamotamab
(N = 60), which yielded an ORR of 50% with 25% CR.51
Single-agent BsAbs are also being investigated in patients
with previously untreated B-NHL, who would exhibit greater
BISPECIFIC ANTIBODIES IN THE TREATMENT OF LYMPHOMA
immune fitness and more consistent CD20 expression without
having been exposed to chemotherapy or rituximab.52 In
patients with newly diagnosed DLBCL unfit for immunoche-
motherapy, mosunetuzumab produced a best ORR of 68% with
42% CR.53 Similar studies are underway in patients with iNHL,
and their results are eagerly awaited (supplemental Table,
available on the Blood website).
Early safety observations and toxicity
management
The safety profile of BsAb has been rather consistent across
trials, and most adverse events (AEs) have been manageable,
with rare treatment interruptions or discontinuations and only 5
fatal events causally linked to drug-related AEs in 2 studies.28,36
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Toxicities related to T-cell overactivation dominated the safety
profile of BsAb. Among these, cytokine release syndrome (CRS)
was the most frequent, occurring in 15% to 80% of patients
depending on the agent, route of administration, and dosing
schedule (Table 3). Clinically, this syndrome presented with any
combination of chills, fevers, skin rash, hypotension, hypoxia,
and confusion, beginning 0.5 to 2 days after BsAb administra-
tion and generally resolving within 1.5 to 3 days. It occurred
most frequently and with the greatest severity during the first
cycle of therapy, and rarely persisted beyond the second cycle,
reflecting conditional, target-dependent T-cell activation.
Grading of CRS was adjudicated according to consensus criteria
originally developed for CAR T-cell therapy.54,55 Most patients
had grade 1 to 2 CRS, which resolved spontaneously or with
minimal intervention, including IV hydration, acetaminophen,
and corticosteroids. Few individuals experienced a more severe
syndrome requiring treatment with tocilizumab, an anti-IL6
antibody, and, occasionally, intensive care unit admission for
close monitoring and vasopressors. No fatalities related to CRS
have been reported to date across CD20xCD3 BsAb trials.
Neurological toxicities potentially related to T-cell over-
activation have been observed with the use of BsAb, including
delirium, dysphasia, tremor, lethargy, difficulty concentrating,
agitation, confusional state, aphasia, depressed level of con-
sciousness, encephalopathy, seizures, or cerebral edema.55
Although the term immune effector cell–associated neurotox-
icity syndrome–like has been used to describe these AEs, the
pathogenesis and clinical findings of neurological toxicity
associated with BsAb and CAR T-cell therapy (for which the
term immune effector cell–associated neurotoxicity syndrome
was coined) may not be overlapping. CAR T-cells are known to
traffic to the CSF, causing increased protein and cytokine
levels,56 and potentially targeting CD19-expressing mural cells
in the brain,57 but IgG-like BsAb are not expected to cross the
blood-brain barrier, and virtually no information is available on
the presence of activated T cells or inflammatory cytokines in
the CSF of these patients. Accordingly, neurological AEs in
BsAb clinical trials have been rare, generally mild, and self-
resolving within hours of their onset.28-30,36
Several mitigation strategies have been pursued to prevent or
minimize the severity of AEs due to T-cell overactivation
(Table 3). A widely implemented approach is referred to as
step-up dosing, where patients are given a small, “priming”
dose followed by an intermediate dose, before receiving the
full dose of the BsAb. In preclinical models, this strategy was
2 FEBRUARY 2023 | VOLUME 141, NUMBER 5 473
 Table 3. Mitigation strategies used in BsAb clinical trials and resulting CRS rates
474

Mitigation strategies during C1 % CRS‡

Trial ID N. Histology, setting Drug(s) Route Full dose, mg SUD Hosp* Other† G1 G2 G3 G4 G5 % serious CRS % toci use
NCT03677154 29 DLBCL, ND MOSUN IV 13.5 (8), 30 (21) Yes Mandatory 17 3 0 0 0 NR 0
2 FEBRUARY 2023 | VOLUME 141, NUMBER 5

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NCT02500407 197 Mixed, R/R MOSUN IV 2.8-40.5 Yes§ Optional only 21 6 1 0 0 7 1.5
in exp. cohorts
90 FL, R/R MOSUN IV 30 Yes Optional 26 17 1 1‖ 0 NR 7.8
39 Mixed, R/R MOSUN SC 45 Yes Optional 11 4 0 0 0 178 10.3
27 Mixed, R/R MOSUN, rapid SUD SC 45 Yes Optional 33 8 0 0 0 4 0

NCT03075696 258 Mixed, R/R GLOFIT IV 0.6-30 Yes§ Mandatory Obin¶ 31 23 4 2 0 36 20% at RP2D
155 DLBCL, R/R GLOFIT IV 30 Yes Mandatory Obin¶ 47 12 3 1 0 NR 32
24 FL, R/R GLOFIT IV 16 (3), 30 (21) Yes Mandatory Obin¶ 63 13 4 0 0 50 8.3
29 FL, R/R GLOFIT, ext. SUD IV 30 Yes Mandatory Obin¶ 35 21 0 0 0 31 21
19 FL, R/R GLOFIT-obin IV 30 Yes Mandatory Obin¶ 53 26 0 0 0 26 26
29 MCL, R/R GLOFIT IV 0.6-30 Yes§ Mandatory Obin¶ 35 21 0 3 0 38 24

NCT03625037 68 Mixed, R/R EPCOR SC 0.0128-60 Yes§ Mandatory Post-dose CS 29 29 0 0 0 NR 0

157 LBCL, R/R EPCOR SC 48 Yes Mandatory Post-dose CS 32 15 2 0 0 NR 14

NCT04082936 40 Mixed, R/R IgM2323 IV 0.5-1000 Yes§ Mandatory 18 5 3 0 0 NR NR

NCT02924402 64 Mixed, R/R PLAMO IV 0.7-450ug/Kg, or 50 Yes§ NR 19 33 <1 <1 0 NR NR

NCT02290951 145 Mixed, R/R ODRON IV 0.5-320 Yes Mandatory Split-dose 36 18 6 1 0 NR NR

NCT03677141 40 DLBCL, ND MOSUN-CHOP IV 30 Yes NR 40 13 0 0 0 NR 5

NCT03467373 31 Mixed, R/R GLOFIT-R-CHOP IV 0.07-30 Yes§ Mandatory GLOFIT from C2 32 13 10 0 0 26 26

26 DLBCL, ND GLOFIT-R-CHOP IV 30 Yes Mandatory GLOFIT from C2 4 4 0 0 0 0 0

NCT04663347 24 DLBCL, ND EPCOR-R-CHOP SC 24 (4), 48 (20) Yes Mandatory Post-dose CS 17 17 4 0 0 NR NR

29 DLBCL, R/R EPCOR-R-DHAX SC 48 Yes Mandatory Post-dose CS 38 28 10 0 0 NR 7
26 DLBCL, R/R EPCOR-GemOx SC 48 Yes Mandatory Post-dose CS 27 38 4 0 0 NR 19

NCT03671018 63 DLBCL (60), FL (3), R/R MOSUN-pola IV 30 Yes Optional 16 2 0 0 0 8 0

NCT03533283 59 Mixed, R/R GLOFIT-pola IV 10 (6), 30 (53) Yes NR GLOFIT from C1D8 29 12 0 0 2 24 11.9

NCT04246086 29 FL, R/R MOSUN-len IV 30 Yes Optional 24 3 0 0 0 14 0

NCT04663347 29 FL, R/R EPCOR-R-len SC 2 (3), 48 (26) Yes Mandatory Post-dose CS 28 14 7 0 0 NR NR

The table separates single-agent studies (upper portion) from combination studies (lower portion). Data generally refer to the CRS episode with highest frequency and/or of the highest grade following BsAb dosing. These varied among trials. Virtually all
patients received acetaminophen, antihistamine, and corticosteroids premedication. The distinction between CTCAE-defined infusion-related reaction and CRS was either not explicitly made or left at the treating physician’s discretion, thus it is possible that the
true incidence of CRS be different than reported in some studies.
C, cycle; CS, corticosteroids; (D)LBCL, (diffuse) large B-cell lymphoma; EPCOR, epcoritamab; esc, escalation; exp, expansion; FL, follicular lymphoma; GLOFIT, glofitamab; G, grade; len, lenalidomide; hosp, hospitalization; MCL, mantle cell lymphoma;
MOSUN, mosunetuzumab; ND, newly diagnosed, NR, not reported; obin, obinutuzumab; ODRON, odronextamab; PLAMO, plamotamab; pola, polatuzumab, RP2D, recommended phase-2 dose; R/R relapsed/refractoy; SC, subcutaneous; SUD, step-up
dosing; toci, tocilizumab.
FALCHI et al

*Prescribed on the day of expected highest risk of CRS.

†In all reported studies, corticosteroids were used as part of the premedication during cycle 1 and, in some cases cycle 2.
‡Incidence as reported by authors, separately reported single components are not listed in this table.
§Performed in only part of the study population, for example, at certain dose levels or in expansion cohorts only.
‖Patient with leukemic phase FL.
¶Generally administered on cycle 1, day 7; defined according to the ASBMT consensus criteria.
shown to reduce peak systemic cytokine release without
significantly compromising tumor cell killing.58 Investigators
have used both rapid (2-step)31 and extended one (4-step)47
dose-escalation schemes. Other preventive measures have
included slower IV infusion,29,36 the use of prophylactic corti-
costeroids during the first few weeks of therapy,30 inpatient
administration of the dose at the highest risk of provoking
CRS,28-30,36 and, in glofitamab trials, single-dose obinutuzumab
pretreatment based on preclinical experiments suggesting that
depleting circulating B cells may dampen T-cell activation,
cytokine release, and subsequent endothelial cell activation.15
Preclinical data also suggested that modulating the affinity for
CD3 may attenuate the severity of CRS while preserving the
efficacy of the BsAb,59 an observation that has not yet been
clinically validated.
Aside from AEs due to T-cell overactivation, the toxicity profile
of BsAb is characterized by neutropenia (15%-33%), hypo-
phosphatemia (13%-29%), anemia (19%-38%) fatigue (18%-
42%), and diarrhea (15%-26%), all predominantly of grade 1 to 2
and reversible.28-30,36,50,51 It should be noted that long-term
BsAb safety data are not yet available, and potential AEs
related to delayed B-cell recovery will need to be ascertained.
BsAb-containing combinations
Preclinical work had demonstrated that, although T-cell
numbers are decreased in patients treated with immunoche-
motherapy, surviving T cells can still be activated and kill lym-
phoma cells when engaged by a BsAb.60 Accordingly, the
lymphoma killing activity of CD20xCD3 BsAb was not signifi-
cantly affected when T-cell cytotoxic agents like cyclophos-
phamide or dexamethasone were coadministered, individually
or in combination, both in vitro and in mice expressing human
CD20 and CD3.34,61 Moreover, BsAb appear combinable with
monospecific anti-CD20 antibodies because they target
partially overlapping epitopes, do not compete for FcγR, and
induce potent target-cell killing at low occupancy rates. Several
studies combining BsAb with cytotoxic chemotherapy were
commenced, and some results have begun to emerge (Table 2
and supplemental Table).
Glofitamab and epcoritamab have been integrated into
standard-of-care platinum-based chemoimmunotherapy plat-
forms for the treatment of patients with R/R aNHL. Clinical
results have been promising (eg, ORR and CR rate of 100% and
86%, respectively, for epcoritamab-R-DHAX,62 and 92% and
60%, respectively, for epcoritamab-gemcitabine, oxaliplatin63)
and registration-directed phase 3 trials are being launched
(supplemental Table).
Both mosunetuzumab and glofitamab have been combined with
the anti-CD79b antibody-drug conjugate polatuzumab vedotin
in patients with R/R DLBCL. The ORR and CR rates of these
combinations were 65% and 48%, respectively, for mosunetu-
zumab and 80% and 51%, respectively, for glofitamab. Although
these results appear similar to those observed in the single-agent
trials, the short follow-up precludes an exhaustive evaluation of
the depth and durability of these responses.64
Additional studies have combined BsAb with immunomodula-
tory agents with the aim of restoring the immune synapse65 and
BISPECIFIC ANTIBODIES IN THE TREATMENT OF LYMPHOMA
potentiating BsAb-dependent cytotoxicity. In patients with R/R
FL, mosunetuzumab and epcoritamab have been combined
with lenalidomide, with or without rituximab. Both combina-
tions exhibited remarkable preliminary activity, with responses
seen in nearly all patients and CR in the majority of them.66-68
These results are still immature, and their long-term perfor-
mance, the role of the addition of rituximab, or the optimal
treatment duration remain to be defined. Nonetheless, phase-
3, registration-directed trials of these combinations have been
launched. Other approaches include combining CD20xCD3
BsAb with other BsAb that deliver costimulatory signals to
engaged T cells, such as those targeting CD137 or CD28
(supplemental Table).
Use of BsAb in the initial management of patients
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with B-cell lymphoma
In patients with newly diagnosed DLBCL, 2 phase 1/2 studies
combining mosunetuzumab or glofitamab with cyclophospha-
mide, doxorubicin, vincristine, and prednisone (CHOP) with or
without rituximab produced positive efficacy signals.69,70 Given
the already high efficacy of standard R-CHOP in unselected
patients with DLBCL, one approach to incorporating BsAb is to
reserve their use to higher-risk individuals. In a study of com-
bined epcoritamab and R-CHOP in 33 patients with DLBCL with
an international prognostic index of 3 to 5, all subjects
responded, and 77% had a CR.71 Another high-risk DLBCL
category includes patients with <2.5 log reduction in circulating
tumor (ct)DNA after 2 cycles of R-CHOP,72 and a study of
glofitamab-R-CHOP in patients with “ctDNA high-risk” DLBCL
is underway. Phase 3 trials comparing BsAb plus R-CHOP–like
platforms to standard immunochemotherapy are expected to
commence. For patients with treatment-naïve FL, trials of
epcoritamab combined with bendamustine and rituximab or
lenalidomide and rituximab are accruing, while studies of
mosunetuzumab as a single agent or in combination with
polatuzumab vedotin or lenalidomide are being initiated
(supplemental Table).
It is worth noting that in combination trials, the addition of BsAb
to chemotherapy has not so far significantly interfered with the
timely delivery of chemotherapy or produced new adverse
safety signals, and the toxicity profile of each combination
largely recapitulated that of its components. Interestingly,
combining potentially T-cell cytotoxic chemotherapy did not
seem to diminish the rate or severity of CRS, suggesting that
BsAb-engaged T cells retain significant inflammatory activity in
the presence of chemotherapy (Table 3).
Biomarkers of response, resistance, and
toxicity
Remarkable activity and the potential for serious CRS represent
the "yin-yang" of BsAb therapy. Consequently, the search for
PD biomarkers of response, resistance, and toxicity has been
intense. Potential mechanisms of BsAb resistance may be
broadly separated into 3 categories, as depicted in Figure 1.
First, selective pressure may drive the activation of programs
that promote immune escape. Loss of the target antigen CD20
is known to occur after anti-CD20 monoclonal antibody ther-
apy.73-75 Although higher baseline CD20 expression was not
clearly associated with the achievement of CR after CD20xCD3
2 FEBRUARY 2023 | VOLUME 141, NUMBER 5 475
 A B
BsAb
CD20
TGF-b
IL-10
PD-L1
Myc
p53
Lymphoma cell
Teff
Figure 1. Mechanisms of resistance to BsAb within the lymphoma microenvironment. Potential mechanisms of resistance to BsAb therapy include (A) tumor cell–intrinsic
mechanisms, such as antigen loss and activation of immune-evasive gene expression programs, (B) T-cell intrinsic mechanisms, including activation of regulatory T-cells,
downregulation of the T-cell receptor, and development of T-cell exhaustion, and (C) T-cell extrinsic mechanisms, including recruitment of immunosuppressive myeloid and/
or stromal cells. CAF, cancer-associated fibroblast; IL-10, interleukin-10; MDSC, myeloid-derived suppressor cell; PD-1, programmed death 1; PD-L1, programmed death
ligand 1; TAM, tumor-associated macrophage; Teff, effector T cell; Texh, exhausted T cell; TGF-b, transforming growth factor beta; Tim-3, T-cell immunoglobulin mucin-3;
Treg, regulatory T cell.
BsAb therapy,45,76 a loss of CD20 was observed in patients with
progressive or recurrent disease and in some cases was asso-
ciated with CD20 gene mutations.52,77 Furthermore, a detailed
analysis of tumor biopsies from patients with DLBCL treated
with glofitamab revealed a somewhat higher frequency of TP53
mutations or overactivated MYC signaling among patients with
progression, suggesting that distinct oncogenic pathways
might be associated with either de novo or acquired resistance
to BsAb.78 Intriguingly, both TP53 mutations79-81 and MYC
amplifications82-84 are known to promote resistance to immu-
notherapy, including CAR T-cell therapy.85
A second mechanism of resistance to BsAb is intrinsic or
acquired T-cell dysfunction within the lymphoma microenvi-
ronment. The landscape of nonmalignant T cells within the
lymphoma microenvironment is diverse and includes both
CD4+ and CD8+ cells with cytotoxic as well as regulatory
functions. Because BsAb-induced CD3-mediated T-cell activa-
tion is by definition nonselective, activation of regulatory or
suppressive T cells within the lymphoma microenvironment
might promote resistance.76 Correlative studies of phase 1 trials
confirmed the preclinical observation that BsAb induce a
rapid and transient decrease in peripheral blood CD3+ cells
(thought to reflect T-cell redistribution),29,30,78 which was more
pronounced in responders,78 and, simultaneously, a dose-
dependent increase in activated (granzyme B+, Tim3+, or
PD-1+) CD8+ and CD4+ T cells,28,29,53 which was sustained with
repeated dosing.30,43,78 However, in ex vivo studies, BsAb
therapy exerted greater tumor killing by peripheral blood than
by intratumoral T cells,86 suggesting that tumor-resident T cells
may be at least in part resistant to BsAb-dependent activation.
This resistance may occur owing to the consequences of
persistent TCR triggering, which is known to downregulate CD3
expression and may desensitize intratumoral T cells to further
BsAb-dependent activity.87 Moreover, chronic TCR triggering
promotes a dysfunctional T-cell phenotype known as T-cell
“exhaustion,” which is associated with blunted antitumor
activity.88 Finally, the lymphoma microenvironment contains
several elements, such as tumor-associated macrophages,
cancer-associated fibroblasts, and myeloid-derived suppressor
cells, all of which can promote immunosuppression. Whether
476 2 FEBRUARY 2023 | VOLUME 141, NUMBER 5
Treg C
MDSC
BsAb
CD20
TAM
-3
Tim
CAF
PD-1
Texh
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and how these cells directly limit BsAb activity remains to be
determined.
Data on clinical and biological predictors of CRS have also
begun to emerge. In one clinical study, pretreatment parameters
such as age, stage, tumor burden, bone marrow involvement,
and the presence of circulating lymphoma B cells were found to
correlate with the risk of CRS.89 Other factors, including a low
in vitro EC50, the dose of the BsAb, and its route of administra-
tion32 may influence this risk. Studies looking at changes in
plasma levels of cytokines like interleukin-2, interleukin-6 inter-
feron gamma, or tumor necrosis factor alfa as a function of
treatment have been largely descriptive, and the correlation
between cytokine levels and CRS is inconsistent.28,30,64,78,89
Conclusions
BsAb, primarily those targeting CD20xCD3, represent a
breakthrough in the treatment of patients with B-NHL and will
likely constitute an important addition to the available thera-
peutic armamentarium. Managing toxicities related to T-cell
overactivation will likely require a learning curve. In this sense,
physician and patient education, better identification of risk
factors for CRS, and further development of prophylaxis and
treatment guidelines will be key to the widespread adoption of
these drugs. Following mosunetuzumab’s approval for R/R FL in
Europe, BsAb are likely to receive additional approvals by
health authorities for patients with R/R B-NHL.
As we learn more about the efficacy and safety of these drugs,
several emerging questions will need to be answered (Table 4).
Although CR rates observed with BsAb in unselected patients
rival those seen with CAR T-cell therapy, a fair appraisal of these
drugs will require additional information on the DORs and on
whether cures are achievable, particularly in patients with aNHL.
BsAb are being increasingly used in combination with other
agents to improve the rate and DORs, and numerous such trials
underway attest to the appeal of this new therapeutic modality.
Similarly, efforts to move their use earlier in the disease course
are accelerating. Understanding the determinants of response
and resistance will be critical for patient selection, optimal
FALCHI et al
Table 4. Synopsis of areas of uncertainty in BsAb research and relative specific challenges

Areas of uncertainty Challenges

Management of T-cell overactivation syndromes Identifying risk factors for CRS
Optimal step-up dosing, drug formulation, prophylaxis
Outpatient administration
Patient and provider education

DOR Optimal duration of BsAb therapy

Predictors of durable response

Moving BsAb to earlier lines of therapy Competitive landscape

Selecting the most appropriate patient populations (eg, high-risk disease)

Optimal combinations Moving beyond cytotoxic agents as partners

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Rational (rather than expedient) combinations

Understanding mechanisms of resistance Identifying actionable tumor-intrinsic resistance mechanisms

Detailed characterization of T-cell function (and dysfunction) during BsAb therapy
Dissecting the role of other players in the lymphoma immune microenvironment

positioning, and future rational combinations. Ultimately, well-
designed clinical trials will be necessary to assess the role of
BsAb in the management of patients with lymphoma and move
their development forward.
Acknowledgment
We are grateful to Terry Helms for creating the illustrations of the bis-
pecific antibodies contained in this article.
has membership on advisory committees of Immunai Inc and receives
consulting fees from Koch Disruptive Industries. G.A.S. has membership
on advisory committees receives consulting fees from AbbVie, Bayer,
Beigene, BMS/Celgene, Epizyme, Hoffmann-La Roche/Genetech,
Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, Molecular Part-
ners, Morphosys, Nordic Nanovector, Novartis, Rapt, Regeneron, and
Takeda; and is a shareholder in Owkin.
ORCID profiles: L.F., 0000-0003-1531-3838; S.A.V., 0000-0002-3100-
1298; G.A.S., 0000-0002-9541-8666.

This work was supported by a grant from the National Institutes of Correspondence: Gilles A. Salles, Lymphoma Service, Department of
Health, National Cancer Institute to the Memorial Sloan Kettering Medicine, Memorial Sloan Kettering Cancer Center, 530 E 74th St, New
Cancer Center (P30 CA008748). York, NY 10021; email: sallesg@mskcc.org.

Authorship
Contribution: All authors designed the research, summarized the data,
wrote, and approved the paper.
Footnotes
Submitted 3 May 2022; accepted 12 October 2022; prepublished online
Conflict-of-interest disclosure: L.F serves as a consultant for Genmab, on Blood First Edition 2 November 2022. https://doi.org/10.1182/
AbbVie, and Hoffmann-La Roche/Genentech; has received research blood.2021011994.
funding from Genmab, AbbVie, and Hoffmann-La Roche/Genetech; and
has membership on advisory committees of ADC Therapeutics. S.A.V. The online version of this article contains a data supplement.

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