Exhibit 10.5

 

SANOFI-AVENTIS AND IMMUNOGEN CONFIDENTIAL

Execution Copy

 

AMENDMENT NO. 2 TO THE

COLLABORATION AND LICENSE AGREEMENT

 

This Amendment No. 2 to the Collaboration and License Agreement (this
“Amendment”) is dated as of December 7, 2007 (the “Amendment Effective Date”) by
and between ImmunoGen, Inc., a Massachusetts corporation with a principal office
at 128 Sidney Street, Cambridge, MA 02139 (“ImmunoGen”), and sanofi-aventis U.S.
LLC, a Delaware limited liability company with offices at 1041 Rte. 202-206,
Bridgewater, NJ 08807 (“Aventis”).  Capitalized terms used but not otherwise
defined herein shall have the meanings ascribed to such terms in the
Collaboration and License Agreement (the “Agreement”) dated as of July 30, 2003
(the “Agreement Effective Date”) by and between ImmunoGen and Aventis
Pharmaceuticals, Inc. (predecessor in interest to Aventis), as amended
August 31, 2006.

 

WHEREAS, on the Agreement Effective Date, ImmunoGen and Aventis entered into the
Agreement for the purpose of collaborating on the identification and validation
of targets for use in the discovery of antibodies and antibody-drug conjugates
in the Collaborative Focus Area (as defined in the Agreement) and in the
development and commercialization of such antibodies and antibody-drug
conjugates; and

 

WHEREAS, the Parties hereto desire to amend the Agreement to provide that
ImmunoGen will develop a Phase IIb/III scale process for manufacturing SAR3419
and Aventis will assist and compensate ImmunoGen, all as set forth in this
Amendment, and to set forth certain additional terms applicable to the
Agreement, as so amended.

 

NOW, THEREFORE, in consideration of the mutual covenants contained herein, and
for other good and valuable consideration, the Parties hereto, intending to be
legally bound, hereby agree as follows:

 

In consideration of the mutual promises and covenants hereinafter set forth
herein, and other consideration, the Parties agree as follows:

 

1.                                      Amendments to Agreement.

 

 

(a)                                 The following new definitions are hereby
added to Article 1 of the Collaboration Agreement:

 

 

“1.25A

“Conjugation Process” means a process for manufacturing SAR3419 by conjugating
its component parts, which is to be developed as part of the Services under this
Agreement.”

 

 

“1.82A

“Project Plan” means the project plan attached hereto as Exhibit C, which
describes the Services, sets forth the Requirements, and includes other
information, terms and conditions relevant to performance of the Services, as
amended and updated by mutual agreement of the Parties.”

 

 

“1.82B

“Project Materials” means any materials, other than Aventis Materials, used by
ImmunoGen in the conduct of the Services.”

 

 

“1.82C

“Project Technology” means any Technology that is developed or conceived by
employees of, or consultants to, ImmunoGen in the conduct of the Services.”

 

 

“1.85D

“SAR3419” means huB4 antibody conjugated to DM4 through the SPDB linker.”

 

 

“1.85E

“Requirements” means any specifications or requirements applicable to the
Services set forth in the Project Plan.”

 

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“1.86A

“Services” means the process development work to be performed by ImmunoGen, as
described in the Project Plan.”

 

(b)                                 The definition of Aventis Materials set
forth in Section 1.10 of the Agreement is hereby amended by adding the following
sentence at the end of the definition:

 

“For purposes of clarity, Aventis Materials includes SAR3419.”

 

(c)                                  The definition of ImmunoGen Materials set
forth in Section 1.49 of the Agreement is hereby amended by adding the following
sentence at the end of the definition:

 

“For purposes of clarity, ImmunoGen Materials includes all Project Materials.”

 

(d)                                 The definition of “ImmunoGen Technology
Improvements” is hereby deleted in its entirety and replaced with the following:

 

“ImmunoGen Technology Improvements” means (a) any Technology which (i) is
developed or conceived by employees of, or consultant to, either Party or
jointly by both Parties, under this Agreement and (ii) (A) is Covered by the
ImmunoGen Patent Rights or (B) is a maytansinoid that is substantially
equivalent to a maytansinoid Covered by an ImmunoGen Patent Right listed on
Schedule 1.50 or (C) is a method of manufacture or use with respect to a
maytansinoid that is substantially equivalent to a method of manufacture or use,
respectively, with respect to a maytansinoid and Covered by an ImmunoGen Patent
right listed on Schedule 1.50 and (b) any Project Technology.”

 

(e)                                  A new Section 4.5 is hereby added to the
Agreement which shall provide as follows:

 

“4.5                         “Process Development Services.”

 

4.5.1                     Project Plan Document.  The Project Plan describes the
Services, and the terms and conditions applicable to the conduct by ImmunoGen of
the Services, under this Agreement.  The Project Plan may be amended by mutual
agreement of the Parties and any updated or amended Project Plan will become
part of this Agreement upon execution by both Parties.  In the event of a
conflict between the terms of this Agreement and any terms of the Project Plan,
the terms of this Agreement shall control.

 

4.5.2                     Performance of Services.  ImmunoGen shall use
Commercially Reasonable Efforts to perform the Services in accordance with this
Agreement, the Project Plan and the Requirements.  Without limiting the
foregoing, ImmunoGen shall (a) make available facilities, utilities, equipment
and computerized systems that are adequate to perform the Services in accordance
with the Project Plan; and (b) provide an adequate number of personnel to
perform the Services, all of whom have appropriate education, training and
experience to do so.  At Aventis’ request, ImmunoGen shall provide Aventis with
resumes or CVs for personnel assigned to perform the Services.  ImmunoGen shall
be responsible for procuring any and all Project Materials, for ensuring that
such Project Materials are suitable for the intended purposes, and for
inspecting, testing, as appropriate, storing and maintaining Project Materials. 
Other than payment of fees under Section 8.47(a), (b) and (c) and reimbursement
of certain out-of-pocket costs under Section 8.4.7(d), ImmunoGen shall be
responsible for all costs and expenses incurred in providing the Services.

 

4.5.3                     Schedule and Adjustments.  If ImmunoGen proposes to
make any proposed changes to its personnel, facilities, utilities or equipment
that are reasonably likely to affect the quality or timing of

 

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its performance of the Services, ImmunoGen shall promptly notify Aventis in
writing of such proposed changes.  If Aventis reasonably determines that any
such proposed changes are likely to materially affect the development and/or
commercialization by Aventis of SAR3419, the implementation of those changes
will be subject to Aventis’ approval, which will not be unreasonably withheld. 
If any delay in completing the Services is due to Aventis’ failure to perform
its obligations under this Agreement, including but not limited to delay in
providing Aventis Materials under Section 4.5.6, then the Project Plan and the
Milestone-Based Fees in Section 8.4.7(c) will be adjusted accordingly to
reasonably account for such delay.

 

4.5.4                     Project Management and Aventis Assistance.  Each Party
shall appoint designees to coordinate the conduct of the Services as appropriate
(the “Project Managers”).  Project Managers will meet on a bi-weekly basis (more
or less frequently if mutually agreed) to assess the progress of the Services. 
Decisions by Project Managers are not binding except to the extent consistent
with the Project Plan or agreed in writing by the Parties.  Aventis shall
provide ImmunoGen with guidance, information and assistance as reasonably
necessary for ImmunoGen to perform the Services, and shall use Commercially
Reasonable Efforts to perform any obligations under any Project Plan related to
such guidance and assistance.

 

4.5.5                     Modifications of Services, Requirements or Project
Plan Document.  If Aventis reasonably determines that modifications to the
Services or any Requirements are necessary, Aventis shall communicate such
proposed modifications in writing to ImmunoGen (the “Proposed Modifications”). 
If ImmunoGen reasonably believes that any such proposed modifications would be a
material change to the Services or the Requirements, then ImmunoGen shall so
inform Aventis, and shall include (a) an estimate of the length of time of any
delay in the schedule as a result of the Proposed Modifications, and/or (b) an
estimate of any revisions to the fees or costs as a result of the Proposed
Modifications.  Subject to the foregoing, (a) ImmunoGen shall use Commercially
Reasonable Efforts to assist Aventis in implementing the Proposed Modifications,
(b) the Parties shall update the schedule in the Project Plan (including the
applicable milestones), and (c) the Parties shall mutually agree on the fees
and/or costs required to implement the Proposed Modifications.  Aventis shall be
responsible for the payment of all such agreed fees and/or costs, as reflected
in the updated schedule in accordance with this Agreement.

 

4.5.6                     Aventis Materials.  Unless otherwise specified in the
Project Plan, Aventis shall deliver to ImmunoGen, at its own expense, the
Aventis Materials in the form and amounts identified in the Project Plan.  For
any Aventis Materials to be procured by ImmunoGen, ImmunoGen shall procure those
Aventis Materials in the form and in amounts identified in the Project Plan and
Aventis shall reimburse ImmunoGen for its costs incurred in making such
procurement under Section 8.4.7(d).

 

4.5.7                     Termination of Services.  The obligation of ImmunoGen
to conduct all or any part of the Services may, subject to Section 4.5.8 below,
be terminated (a) by Aventis, at any time, and for any reason or no reason, by
providing written notice of termination to ImmunoGen at least thirty (30) days
prior to the date of termination, which notice shall specify the scope of the
terminated Services; and (b) by either Party, by providing written notice of
termination to the other Party at least thirty (30) days after having provided
to the other Party notice of such Party’s material breach of this Agreement,
unless such material breach has been cured within the thirty (30) day period
after the initial notice of breach; provided, however, that when a Party
allegedly in breach disputes in good faith that a breach has occurred, then both
Parties shall continue performance during the pendency of any dispute resolution
procedure for up to a maximum of six (6) months after notice of an alleged
material breach.

 

4.5.8                     Obligations Upon Termination or Expiration of
Services.

 

(a)                                 Payment by Aventis:  Except with regard to
termination by Aventis as a result of the uncured material breach of ImmunoGen,
upon termination of the Services as provided in Section

 

3

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4.5.7, Aventis shall pay ImmunoGen: (i) the Service Fees described in
Section 8.4.7(a) that were authorized to be incurred and were actually incurred
prior to termination; (ii) reimbursable costs not already paid, to the extent
such costs already have been incurred and (iii) any early termination fee as
calculated under subsection (b) below.

 

(b)                                 Early Termination Fee:  If Aventis
terminates the Services under Section 4.5.7(a) above at any time on or before
ten (10) months from the date of initiation of the Services for any reason other
than technical failure with respect to, or adverse clinical results which would
preclude proceeding with, the further development of SAR3419, then Aventis shall
pay ImmunoGen a termination fee of three hundred and fifty thousand dollars
($350,000) no later than the effective date of termination.

 

4.5.9                     Subcontracting and Use of Contract Manufacturing
Organizations.  ImmunoGen shall not subcontract any of its obligations to
conduct Services under this Agreement without Aventis’ prior written consent,
which will not be unreasonably withheld or delayed.  To the extent Aventis
Materials are required for performance under an authorized subcontract, Aventis
either shall provide the Aventis Materials directly to the authorized
subcontractor, or shall authorize ImmunoGen to provide the Aventis Materials to
the authorized subcontractor, in either case subject to an appropriate material
transfer agreement or other agreement between Aventis and the authorized
subcontractor.”

 

(f)                                   A new Section 8.4.7 is hereby added to the
Agreement which shall provide as follows:

 

“8.4.7               Service Fees; Costs.

 

(a)                                 Service Fees.  In consideration of
ImmunoGen’s performance of the Services, Aventis shall pay to ImmunoGen fees,
based on hours worked by ImmunoGen employees performing the Services, at a rate
equal to $176.14 per hour or $310,000 per FTE per year (the “Service Fees”).

 

(b)                                 Cost Reimbursement.  Aventis shall reimburse
ImmunoGen for the cost incurred by ImmunoGen in obtaining approved quantities of
DM4 or SPDB for performance of the Services based on ImmunoGen’s standard cost
of such materials, which will be included in the Project Plan. Prior to
obtaining any such DM4 or SPDB, ImmunoGen shall notify Aventis of the quantities
needed and shall receive approval from Aventis.  Notwithstanding the
foregoing, ImmunoGen shall have no obligation to provide Aventis with any
quantities of DM4 or SPDB in excess of the amount set forth in the Project Plan
unless mutually agreed upon in writing.  Aventis shall be solely responsible for
reimbursing ImmunoGen for the cost of any Aventis Materials procured directly by
ImmunoGen (if any).

 

(c)                                  Milestone-Based Fees.  Aventis shall pay
ImmunoGen a milestone-based fee of $500,000 upon mutual agreement that conjugate
has been manufactured at a 2-5 gram scale and meets the target requirements
agreed to in the Project Plan within the time indicated.  In the event that
Aventis reasonably disagrees with the achievement of any such milestone, it
shall so notify ImmunoGen in writing within thirty (30) days.  Within ten
(10) business days of any such notice by Aventis, the Parties shall use
reasonable efforts to resolve the dispute.

 

(d)                                 Invoices and Payment Terms.  Prior to
payment by Aventis of the payments due under this Agreement, ImmunoGen must
submit an invoice to Aventis which shall reference the applicable purchase order
number (each, an “Invoice”).  ImmunoGen shall generate Invoices for all fees and
cost reimbursements.  Invoices for Service Fees and for cost reimbursements
shall be generated quarterly and provided to Aventis promptly after the end of
the Calendar Quarter in which the fees were incurred; invoices for the
milestone-based fee described above will be generated any time after completion
of the milestone (as completion is determined under the Project Plan and
Section 8.4.7(c)).  Each Invoice shall be addressed to:  sanofi-aventis U.S. LLC
Attention: Accounts Payable Department

 

4

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1041 Route 202-206 P.O. Box 5915 Bridgewater, NJ 08807-0800.  Invoices for cost
reimbursement shall include appropriate reasonable documentation of costs
incurred; Invoices for Service Fees shall detail the personnel providing
Services and the number of FTEs/hours spent in performing Services, as
calculated in accordance with Section 8.4.7(a), during the quarter for which the
Invoice applies.  Aventis shall pay Invoices within thirty (30) days after
receipt of each Invoice .  Receipt or acceptance by Aventis of any Invoices
under this Agreement will not preclude Aventis from questioning the correctness
of the underlying information at a later date, or from exercising its rights
under Section 8.4.7.  If any undisputed inconsistencies or mistakes are
discovered in an Invoice, the Parties shall make immediate adjustment, by
reimbursement or credit, as applicable.  Invoices that remain unpaid more than
thirty (30) days beyond the scheduled payment due date may be subject to an
interest charge equal to one percent (1%) per month (twelve percent (12%) per
annum), calculated from the scheduled payment due date forward; provided that in
no event shall such annual rate exceed the maximum interest rate permitted by
law in regard to such payments.  Such payments when made shall be accompanied by
all interest so accrued.  All payments shall be made by wire transfer of
immediately available funds to the following account:

 

Investor’s Bank & Trust Co.

ABA (routing): 011001438

F/C Client Funds # 569530395

Account: 020208420015

Account Title:  ImmunoGen, Inc.

 

(e)                                  Records Maintenance.  ImmunoGen shall
maintain all records and accounts pertaining to the Services under this
Agreement for a period of at least three (3) years from the date of final
payment for the Services, or longer if required by law.  At the request of
Aventis, upon at least ten (10) business days’ prior written notice, but no more
often than once per calendar year, and at its sole expense, ImmunoGen shall
permit an independent certified public accountant selected by Aventis and
reasonably acceptable to ImmunoGen to inspect (during regular business hours)
the relevant records required to be maintained by ImmunoGen under this
Section 8.4.7.  To the extent requested by ImmunoGen, the accountant shall enter
into a confidentiality agreement with both Parties reasonably acceptable to
each.  The results of any such audit shall be made available to both Parties. 
Aventis agrees to treat the results of any such accountant’s review of
ImmunoGen’s records under this Section 8.4.7 as Confidential Information of
ImmunoGen subject to the terms of Section 5.”

 

(f)                                   A new Exhibit C shall be added to the
Agreement which shall be in the form of Exhibit C attached hereto.

 

2.                                      Miscellaneous.  The Parties hereby
confirm and agree that, except as amended hereby, the Agreement remains in full
force and effect and is a binding obligation of the Parties hereto.  This
Amendment may be executed in counterparts, each of which shall be deemed an
original, but all of which together shall constitute one and the same
instrument.

 

[Remainder of page intentionally left blank.]

 

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IN WITNESS WHEREOF, the Parties have caused this Amendment to be duly executed,
effective as of the Amendment Effective Date, by their respective duly
authorized officers.

 

SANOFI-AVENTIS U.S., LLC

 

IMMUNOGEN, INC.

 

 

 

 

 

 

By:

/s/ Thomas G. Metcalf

 

By:

/s/ John Lambert

Name:

Thomas G. Metcalf

 

Name:

John Lambert

Title:

Site Director

 

Title:

Senior Vice President

Date:

13 DEC 2007

 

Date:

07 DEC 2007

 

 

 

 

 

 

SANOFI-AVENTIS U.S., LLC

 

 

 

 

 

 

 

 

By:

/s/ Paul Darno

 

 

Name:

Paul Darno

 

 

Title:

Finance

 

 

Date:

12/13/07

 

 

 

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Exhibit C

 

PROJECT PLAN

 

SAR3419 Phase IIb/Phase III Conjugation Process Development

 

Project Stages & Key Deliverables

 

stage

 

Description

 

duration

 

deliverables

 

Scheduled
completion

I

 

Replace four step process with three step process

 

3 months

 

Process steps identified 2 x 1g batches

 

3 months from start of project

II

 

Process siting

 

8 months

 

Initial process description: Preliminary Process Flow Diagram (PFD)
Preliminary Process Transfer Document (PTD)

 

8 months from start of project

III

 

Demonstration batches

 

2 months

 

2 x 2 — 5g demonstration batches Process Flow Diagram
Process Transfer Document

 

10 months from start of project

IV

 

Process transfer to CMO

 

6 months

 

Approved batch record

 

13 months from start of project

 

Project Timeline: Schedule

 

 

 

Month #

 

 

1

 

2

 

3

 

4

 

5

 

6

 

7

 

8

 

9

 

10

 

11

 

12

 

13

 

14

 

15

Replace four step process

 

X

 

X

 

X ¨

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Process siting

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Demonstration Batches

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

X ¨

 

 

 

 

 

 

 

 

 

 

Transfer to CMO

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

 

 

 

 

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¨Go/no-go decision based upon comparability

 

Timing for transfer to CMO assumes transfer of Phase 1 SAR3419 process to the
same CMO has been successfully completed.

 

Team Communication

 

The joint development team expects to have biweekly teleconferences and
bimonthly face to face meetings or others as deemed necessary. A meeting agenda
will be agreed to and provided prior to each meeting. Meeting slides and data
will be provided prior to each meeting as needed. Meeting action items

 

Exhibit C-1

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and follow up will be provided following each meeting as needed. The team will
utilize a joint shared repository site to store project documents.

 

Requirements & Scale

 

Demonstration Scale: 2 - 5g or as determined appropriate by process requirements
and equipment limitations.

 

For both process and product requirements, it is assumed that the
characteristics and quality of the huB4 antibody will be equivalent to the
antibody currently in use for the phase I process.  Any changes to the antibody
manufacturing process that could compromise meeting the targeted Phase IIb
specifications will not be implemented during the term of this study without
mutual consent.

 

Process Requirements: The process used to generate the final 2 x 2 — 5g batches
should meet the following requirements:

 

1)             Small molecule clearance (DMA, PySH, PBA, NHS, DM4)

2)             Process scalability:

a)             Initial target is a 200 — 500g (starting antibody) process,
scalable to 1 — 2kg

b)             Buffer volume optimized

c)              Impact of materials of construction understood, removal of
halides

d)             Process kinetics

i)                 Modification and conjugation durations

ii)              Hold times (to allow for manufacturing flexibility)

3)             Overall process yield should be ~ 80% (current ~ 70%) if possible

 

Product Requirements: The conjugate drug substance should be comparable to the
Phase I material, with the exception of:

 

1)

SDS PAGE. sanofi-aventis may implement a quantitative test

2)

SEC. Target for monomer increased from > 90.0% to > 95.0%

3)

Target concentration increased from 1.0 mg/mL +/- 20% to 5.0 mg/mL +/- 10%

4)

Target D/A 3.7 +/- 0.5 for specification; Process target is 3.7 +/- 0.3

5)

Target free drug lowered from < 0.15% (as % of total protein, equivalent to < 8%
relative to total drug) to < 0.10% (as % of total protein, equivalent to < 5%
relative to total drug) for specification. Target for process is < 0.02% (as %
of total protein, equivalent to < 1% relative to total drug) at t0 by release
assay.

6)

Target for binding assay to be narrowed. Parties will agree on new
specifications, which will be adapted during course of process and assay
development.

 

For SEC, concentration, D/A and Free Drug, evaluation will be performed using
existing assays. Sanofi-aventis will be responsible for development (as
necessary) and performance of the binding assay and may also develop assays for
additional attributes, e.g. solvents (in addition to DMA); naked antibody;
charge heterogeneity; and unreacted linker. As such assays are developed,
sanofi-aventis should use them to test representative samples from the process
development work. See Table 1 at the end of this document for additional
breakdown of proposed analytical responsibilities.

 

STAGE I: Replace four step process with three step process

 

Purpose:                                              To demonstrate feasibility
of removing the purification step for modified antibody that is part of the
current (Phase 1) process.

 

Exhibit C-2

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Activities:

 

1)

Evaluate available in process assays (e.g. free drug, NHS, PBA, PySH, free
linker), further develop if necessary

2)

Investigate pH/temperature/antibody concentration/solvent concentration for
modification and conjugation reactions.

3)

Investigate kinetics of linker degradation, assess impact of degradation
products

4)

Investigate kinetics of DM4 degradation, assess impact of degradation products

5)

Determine amounts of SPDB and DM4 required

6)

Perform 2 x 1g scale up runs to assess feasibility of three step process &
preliminary impact on stability (test particles at t=0)

7)

Compare material produced by three and four step processes

 

Deliverables:

 

S-A:

15 g antibody

 

1 g DM4

 

0.5 g SPDB

 

Analytical testing beyond IMGN responsibility as described in Table 1

 

 

IMGN:

Identified process steps

 

2 x 1g batches

 

Weekly to biweekly update reports

 

Summary chart on 3-step process

 

Preliminary development report (delivered at end of month 4)

 

Duration:                                         3 months.  This assumes that
the analytical results from sanofi-aventis are available in a timely manner. 
Unless otherwise agreed in the biweekly meetings, timely execution will be
defined as ten (10) business days for receipt of the data by ImmunoGen.

 

IMGN FTE:                           Average of 4 FTE’s in Process and 2 FTE’s in
Analytical (may not be evenly distributed over duration of this phase of
project)

 

Go / No Go decision on further optimization of this process will be taken based
on comparability data of 1g demo batches with Ph I reference material. In case
material is not comparable, parties will meet to decide how development program
could be modified to meet the objective.

 

STAGE II: Process siting

 

Purpose:                                              To define siting
requirements for the pivotal/commercial manufacturing facility. This includes
the initial definition of the process operating parameters that impact the
facility footprint and long lead time equipment to be purchased by the
commercial CMO.

 

Activities:

1)

Complete assessment of in process assays, provide analytical support to process

2)

Buffer requirements — IMGN will identify buffer composition and volume
requirements. Factors that will be considered include protein concentration,
solvent concentration, buffer volume and removal of halides (stainless steel
compatibility)

3)

Optimization of SPDB and DM4 amounts

4)

Optimization of reaction time, solvent concentration, temperature and pH (for
modification and conjugation reactions)

 

Exhibit C-3

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5)

TFF assessment — IMGN will perform the necessary studies to optimize TFF steps
(currently expected to be used for initial processing of antibody prior to
modification and for final formulation step). Factors evaluated will include

 

a)             Determine C bulk, TMP, Feed Flow Rate, membrane type and size.

 

b)             Product aggregation profile — Assess if aggregation occurs during
processing and minimize as feasible. Demonstrate small molecule removal that is
consistent with a robust process.

6)

Chromatography assessment — IMGN will perform the necessary steps to optimize
the chromatography step expected to be used for purification of conjugate,
especially with respect to load, yield, purity (removal of conjugate aggregates
and low molecular weight species).

7)

Process Kinetics- to broadly understand impact of addition rate and mixing.

8)

Hold times — define acceptable in process hold times to enhance operational
flexibility

9)

All filtration steps will be appropriately sized

10)

TFF & chromatography reuse will be tracked.

 

Deliverables:

 

S-A:

100g antibody

 

6 g DM4

 

3.5 g SPDB

 

Preliminary formulation, minimally base buffer (by month 4)

 

Analytical testing beyond IMGN responsibility as described in Table 1

 

 

IMGN:

Laboratory samples (mgs to grams)

 

Weekly update reports

 

Initial Process Flow Diagram (PFD)

 

Initial Process Transfer Document (PTD)

 

Reports on development and performance of in process assays

 

Process performance and product quality data demonstrating that process and
product meet requirements as indicated in the requirements and scale section.

 

 

Duration:

8 Months. This assumes that the analytical results from sanofi-aventis are
available in a timely manner. Unless otherwise agreed in the team meetings.
timely execution will be defined as ten (10) business days for receipt of the
data by ImmunoGen.

 

 

IMGN FTE:

Average of 4 FTE’s in Process and 1 FTE’s in Analytical (may not be evenly
distributed over duration of this phase of project)

 

STAGE III:  Demonstration Batches

 

Purpose:                                              To demonstrate the
reproducibility of the process using target reaction conditions, target
chromatography conditions and target TFF conditions.  A protocol for the
demonstration batches will be formally approved to insure that the requirements
for a scaleable process have been met.  During the time required for this
evaluation and protocol approval, the “clock will stop” on the ten month time
frame for delivery of the success milestone.  The milestone timing will resume
once the demonstration batch manufacture is initiated.

 

Exhibit C-4

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Activities:

 

 

 

 

1)             Perform 2 x 2-5 gram batch runs

 

 

Deliverables:

 

 

 

S-A:

4 - 10 g antibody

 

0.5 g DM4

 

0.5 g SPDB

 

All materials generally representative of Phase II quality

 

Analytical testing beyond IMGN responsibility as described in Table 1

 

 

IMGN:

Process Transfer Document

 

Process Flow Diagram

 

Development report summarizing Stages I-III (delivered at end of month 12)

 

2 month accelerated stability summary of demo batches (delivered at end of month
13)

 

Duration:                                         2 months.  This assumes that
the analytical results from sanofi-aventis are available in a timely manner. 
Unless otherwise agreed, timely execution will be defined as ten (10) business
days from receipt of samples for testing to receipt of the analytical data by
ImmunoGen.

 

IMGN FTE:                           Average of 1.5 FTEs in Process and 1 FTEs in
Analytical (may not be evenly distributed over duration of this phase of
project)

 

Go / No Go decision on the continuation of the development program will be taken
based on comparability data of 2-5g demo batches with Ph I reference material,
as set forth in Table 2. In case material is not comparable, parties will meet
to decide how development program could be modified to meet the objective.

 

Success Milestone:  A demonstration batch of at least 2g scale which meets the
targets and specifications described in the “Requirements and Scale” section
above, unless process development data justifies an exception, will be the basis
for a milestone payment of $500,000 if this is accomplished within ten months of
the initiation of Stage 1 work with the projected number of FTEs.  ImmunoGen
will provide formal notification of initiation of Stage 1 work within 4 weeks of
execution of the Amendment.  If the demonstration batch is delayed due to
factors controlled by sanofi-aventis, such as not receiving the needed materials
or analytical data from sanofi-aventis, this date may be modified by mutual
agreement.

 

STAGE IV: Process transfer to CMO

 

Purpose:                                              To transfer the commercial
process from IMGN to the commercial CMO.

 

Activities:

IMGN:                                                         Provide
documentation and answer questions from sanofi-aventis and CMO (including: batch
records and relevant SOP’s from current cGMP process; process flow diagram;
process transfer document; in process test methods)

Technology Transfer to CMO during the Demonstration Batches if required

Participate in tech transfer visit(s) to CMO if required

Exchange and analysis of samples and technical information with CMO (during
CMO’s initial scale-up runs and engineering runs)

Review initial Master Batch Record

 

Exhibit C-5

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S-A:                                                                        With
CMO, select and purchase equipment and raw materials, including selection and
any necessary qualification of vendors

Transfer of required release testing methods

Analytical testing (release and characterization) not performed by the CMO

Review of SOP’s from CMO, including instructions for make-up of buffers

Overall project management (coordination of activities and timeline management)

 

Deliverables:                     Completion by CMO of approved batch records
required for manufacture of material for pivotal trials.

 

Duration:                                         Assuming successful transfer
of Ph 1 SAR3419 process to the CMO, transfer of commercial process should be
complete six months from start of transfer

 

IMGN FTE:                           Depending on scope, average of 1 FTE’s in
Process and 1 FTE’s in Analytical (may not be evenly distributed over duration
of this phase of project).

 

Exhibit C-6

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Total FTE Requirement at ImmunoGen

 

Stages I — IV (up to and including process transfer to CMO) are estimated to
take 13 months.

 

 

Average of 4.5 FTE in Process Science and Engineering (includes Deb Meshulam and
Godfrey Amphlett)

 

Average of 1.5 FTE in Analytical and Pharmaceutical Sciences (analytical
resources only)

 

Estimated Materials Requirements (Stages I — IV)

 

 

 

Ab (gm)

 

DM4 (gm)

 

SPDB (gm)

Month 0

 

15

 

1

 

0.5

Month 3

 

50

 

3

 

1.8

Month 6

 

50

 

3

 

1.8

Month 9

 

4-10

 

0.5

 

0.5

Month 12

 

0

 

0

 

0

 

It is understood that sanofi-aventis intends to provide these materials. If
necessary, ImmunoGen would be able to provide DM4 at a cost of $46,000 per gram,
but would not be obligated to provide any amount in excess of 3 g.

 

Travel Expenses

 

Expenses for IMGN personnel to travel to CMO for tech transfer will be paid by
sanofi-aventis and will require prior approval of projected travel expenses from
sanofi-aventis.

 

Exhibit C-7

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Table 1 SAR3419 Commercial Process Development — Proposed Responsibility for
Analytical Testing

 

 

 

IMGN

 

sanofi-aventis(1)

In Process/Process Characterization

 

Protein Concentration

 

Quantitative SDS-PAGE

 

 

Linker/Antibody

 

 

 

 

Drug/Antibody

 

 

 

 

Protein monomer (SEC)

 

 

 

 

Turbidity

 

 

 

 

PySH/other linker species

 

 

 

 

DMA

 

 

 

 

Free DM4 (+ related species)

 

 

 

 

In use tests for selected RM’s

 

 

Conjugate “Release” (2)

 

Protein Concentration

 

Binding

 

 

Drug/Antibody

 

Any additional testing required by sanofi-aventis

 

 

Protein monomer (SEC)

 

 

 

 

Free DM4 (+ related species)

 

 

 

 

Unconjugated linker

 

 

Product Characterization

 

Mass Spec (whole antibody, deglycosylated) — for drug distribution and
non-quantitative naked Ab

 

Naked Antibody

 

 

 

 

Other solvents (if required by sanofi-aventis)

 

 

 

 

Charge heterogeneity

 

 

 

 

Any additional testing required by sanofi-aventis

Other

 

 

 

All DM4 and SPDB release and characterization testing(3)

 

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(1) If quantitative spec is required, sanofi-aventis will need to assay in
process samples with short turnaround to ensure that development efforts will
enable target to be met.  Choice of relevant samples to be analyzed and assays
to be performed will be mutually agreed. Timely execution will be defined as ten
(10) business days from receipt of samples for testing to receipt of the
analytical data by ImmunoGen unless otherwise mutually agreed upon

 

(2) At IMGN, these “Release” assays will be performed in the Process Sciences
group. We will use assays used in Development for other conjugates, with no
additional development.  Assays may differ from those used in QC.

 

(3) Includes weight/weight tests, as well as analytical investigation of any lot
to lot differences uncovered during use testing at IMGN.

 

Exhibit C-8

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Table 2 SAR3419 Phase I acceptance criteria (as 1 mg/mL solution; microbial
contaminants and bacterial endotoxin do not apply)

 

Test

 

Acceptance criteria

Appearance

 

Liquid, may contain white to off-white particulates

Color

 

Colorless

Identification (Western Blot)

 

Conforms to reference

Purity (SDS-PAGE reduced)

 

 

Sum of light and heavy chains

 

³ 90.0 %

Purity (HPLC-SEC)

 

 

Area percent of monomer

 

³ 90.0 %

Assay (UV)

 

 

Protein concentration

 

0.8 to 1.2 mg/mL

Assay (ELISA)

 

 

Relative Potency by Binding

 

50 to 200 %

In vitro Cytotoxicity assay

 

 

Relative Potency

 

40 to 250 %

Ratio Drug/Antibody (UV)

 

2.6 to 4.4

Total of Free Maytansinoid (HPLC)

 

 

Percentage to total DM4 content

 

£ 8.0 %

Residual solvents

 

 

N,N Dimethylacetamide (DMA) (HPLC)

 

£ 1090 ppm

Ethanol (GC)

 

£ 0.5 %

Hexane isomers (GC)

 

£ 290 ppm

pH

 

5.3 to 5.7

 

Exhibit C-9

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